IL10

UniProt ID: P22301
Organism: Homo sapiens
Review Status: DRAFT
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Gene Description

IL-10 (Interleukin-10, also known as Cytokine Synthesis Inhibitory Factor/CSIF) is the prototypical anti-inflammatory cytokine and founding member of the IL-10 family. It is a secreted homodimeric four-helix-bundle cytokine (~36 kDa dimer) that signals through a heterotetrameric receptor complex comprising two IL-10RA (ligand-binding) and two IL-10RB (signal-transducing) chains. Receptor engagement activates JAK1 (via IL-10RA) and TYK2 (via IL-10RB), leading to STAT3 phosphorylation, dimerization, nuclear translocation, and transcription of anti-inflammatory target genes (e.g., SOCS3, IL1RN). IL-10 is produced by multiple immune cell types including monocytes/macrophages, dendritic cells, T cell subsets (Th1, Th2, Treg), B cells, and NK cells. Its principal function is to suppress inflammatory responses by inhibiting pro-inflammatory cytokine production (TNF, IL-1, IL-6, IL-8, IL-12) in monocytes/macrophages, downregulating MHC class II expression and co-stimulatory molecules, and limiting T cell activation. IL-10 also has immunostimulatory effects on B cells (promoting proliferation, differentiation, and immunoglobulin production) and CD8+ T cells in certain contexts. Loss-of-function mutations in IL10 or IL10R cause very-early-onset inflammatory bowel disease (VEO-IBD), establishing IL-10 signaling as essential for intestinal immune homeostasis.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0006955 immune response
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA annotation for immune response. IL-10 is a central immunomodulatory cytokine involved in both innate and adaptive immune responses. The phylogenetic inference is well-supported by extensive literature on IL-10 across vertebrates.
Reason: IL-10 is definitively involved in immune response; this is one of its most fundamental roles. The IBA annotation is well-supported by conserved function across vertebrate IL-10 orthologs and extensive experimental evidence in human, mouse, rat, and zebrafish (PMID:1940799, deep research review).
GO:0005125 cytokine activity
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA annotation for cytokine activity. IL-10 is a prototypical cytokine that signals through the IL-10 receptor complex to activate JAK-STAT signaling.
Reason: Cytokine activity is the core molecular function of IL-10. It is the founding member of the IL-10 cytokine family and signals through its receptor complex to mediate its biological effects. This is well-established across all orthologs (PMID:1940799, UniProt P22301).
GO:0005615 extracellular space
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA annotation for extracellular space localization. IL-10 is a secreted cytokine that functions in the extracellular space by binding cell-surface receptors.
Reason: IL-10 contains a signal peptide (residues 1-18) and is secreted. It functions as a soluble homodimer in the extracellular space where it engages the IL-10R complex on target cells (UniProt P22301, deep research review).
GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA annotation for positive regulation of JAK-STAT signaling. IL-10 signals through JAK1/TYK2 to activate STAT3 phosphorylation.
Reason: This is a core aspect of IL-10 signaling. Binding to IL-10RA/IL-10RB activates JAK1 and TYK2, leading to STAT3 phosphorylation, which is the canonical downstream signaling pathway (PMID:16982608, deep research review).
GO:0050728 negative regulation of inflammatory response
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA annotation for negative regulation of inflammatory response. IL-10 is the prototypical anti-inflammatory cytokine.
Reason: This is the single most characteristic function of IL-10. It suppresses pro-inflammatory cytokine production, downregulates MHC class II, and limits inflammatory responses. Conserved across vertebrate orthologs (PMID:1940799, PMID:10443688, deep research review).
GO:0140105 interleukin-10-mediated signaling pathway
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA annotation for IL-10-mediated signaling pathway. IL-10 is the ligand that initiates this pathway.
Reason: IL-10 is the defining ligand for the IL-10-mediated signaling pathway. This is essentially tautological for the IL-10 protein itself and well-supported by phylogenetic inference (deep research review).
GO:0005125 cytokine activity
IEA
GO_REF:0000120 		ACCEPT
Summary: IEA annotation for cytokine activity, consistent with the IBA annotation and multiple IDA annotations for the same term.
Reason: Redundant with IBA and IDA annotations but correct. IL-10 is unambiguously a cytokine (UniProt P22301, PMID:1940799).
GO:0005576 extracellular region
IEA
GO_REF:0000120 		ACCEPT
Summary: IEA annotation for extracellular region. IL-10 is a secreted protein.
Reason: Broader than extracellular space (GO:0005615) but still correct. IL-10 is secreted and functions in the extracellular region (UniProt P22301).
GO:0005615 extracellular space
IEA
GO_REF:0000120 		ACCEPT
Summary: IEA annotation for extracellular space, consistent with IBA annotation.
Reason: Redundant with IBA annotation but correct. IL-10 is a secreted cytokine found in extracellular space (UniProt P22301).
GO:0006955 immune response
IEA
GO_REF:0000120 		ACCEPT
Summary: IEA annotation for immune response, consistent with IBA annotation.
Reason: Redundant with IBA annotation but correct. IL-10 is a key immune response cytokine (PMID:1940799).
GO:0005515 protein binding
IPI
PMID:11485736
Crystal structure of the IL-10/IL-10R1 complex reveals a sha... 		MODIFY
Summary: IPI protein binding annotation based on interaction with IL-10RA (Q13651). PMID:11485736 likely describes IL-10/IL-10RA interaction studies.
Reason: The interaction between IL-10 and IL-10RA is physiologically critical and well-characterized, but "protein binding" is too vague. This should be annotated as interleukin-10 receptor binding (GO:0005141) which more precisely captures the functional nature of this interaction.
Proposed replacements: interleukin-10 receptor binding
Supporting Evidence:
PMID:11485736
Interleukin 10 (IL-10) is a dimeric cytokine that plays a central role in suppressing inflammatory responses. These activities are dependent on the interaction of IL-10 with its high-affinity receptor (IL-10R1).
GO:0005515 protein binding
IPI
PMID:12513909
Comparison of interleukin-22 and interleukin-10 soluble rece... 		MODIFY
Summary: IPI protein binding based on interaction with IL-10RB (Q08334) and IL-10RA (Q13651). PMID:12513909 compares IL-22 and IL-10 soluble receptor complexes.
Reason: IL-10 binds both IL-10RA and IL-10RB as part of its receptor complex. "Protein binding" is uninformative; should be interleukin-10 receptor binding (GO:0005141).
Proposed replacements: interleukin-10 receptor binding
Supporting Evidence:
PMID:12513909
IL-22 and IL-10 require different ligand-specific receptor chains (IL-22R and IL-10R1) but share a second receptor chain (IL-10R2) to initiate cellular responses.
GO:0005515 protein binding
IPI
PMID:15837194
Same structure, different function crystal structure of the ... 		MODIFY
Summary: IPI protein binding based on interaction with IL-10RA (Q13651).
Reason: Another IL-10/IL-10RA interaction. Should be annotated as interleukin-10 receptor binding (GO:0005141) for specificity.
Proposed replacements: interleukin-10 receptor binding
Supporting Evidence:
PMID:15837194
These functional differences have been correlated with the approximately 1000-fold lower affinity of vIL-10, compared to hIL-10, for the IL-10R1 receptor chain.
GO:0005515 protein binding
IPI
PMID:20462497
Structure and mechanism of receptor sharing by the IL-10R2 c... 		MODIFY
Summary: IPI protein binding from PMID:20462497, which describes the structure and mechanism of receptor sharing by IL-10R2 (IL-10RB) common chain. Interaction with Q08334 (IL-10RB) and Q13651 (IL-10RA).
Reason: This paper provides structural evidence for IL-10 binding its receptor chains. Should be annotated as interleukin-10 receptor binding (GO:0005141).
Proposed replacements: interleukin-10 receptor binding
Supporting Evidence:
PMID:20462497
IL-10R2 is a shared cell surface receptor required for the activation of five class 2 cytokines (IL-10, IL-22, IL-26, IL-28, and IL-29) that play critical roles in host defense.
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome 		REMOVE
Summary: IPI protein binding from the HuRI (Human Reference Interactome) high-throughput yeast two-hybrid study (PMID:32296183). Interacting partners include O76003, P0DPK4, P25490, P60410, Q8IUG1, Q9BYQ7 -- several of which are keratin-associated proteins or other unlikely interaction partners for a secreted cytokine.
Reason: PMID:32296183 is a large-scale Y2H screen. The interacting partners detected (keratins, KRTAP proteins) are likely non-physiological false positives for IL-10, which is a secreted extracellular cytokine. These interactions lack biological plausibility and are not supported by any other evidence.
Supporting Evidence:
PMID:32296183
A reference map of the human binary protein interactome
GO:0005515 protein binding
IPI
PMID:16982608
Conformational changes mediate interleukin-10 receptor 2 (IL... 		MODIFY
Summary: IPI protein binding with IL-10RA (Q13651) from PMID:16982608. This paper likely describes IL-10 structural biology and receptor interaction.
Reason: IL-10/IL-10RA interaction. Should be interleukin-10 receptor binding (GO:0005141).
Proposed replacements: interleukin-10 receptor binding
Supporting Evidence:
PMID:16982608
Interleukin-10 receptor 2 (IL-10R2) is a critical component of the IL-10.IL-10R1.IL-10R2 complex which regulates IL-10-mediated immunomodulatory responses.
GO:0001818 negative regulation of cytokine production
IEA
GO_REF:0000107 		ACCEPT
Summary: IEA transfer from rat Il10 (P29456). IL-10 is well-established as a negative regulator of cytokine production.
Reason: This is a core function of IL-10. It was originally named Cytokine Synthesis Inhibitory Factor (CSIF) precisely because it inhibits cytokine production by monocytes (PMID:1940799). The IEA transfer is well-supported.
GO:0001938 positive regulation of endothelial cell proliferation
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: IEA transfer from mouse Il10 (P18893) for positive regulation of endothelial cell proliferation. This is a non-immune pleiotropic effect.
Reason: While IL-10 has been reported to have effects on endothelial cells, this is a downstream pleiotropic effect rather than a core function. IL-10 is primarily an immune regulatory cytokine. The annotation represents an over-annotation of a secondary effect observed in specific experimental conditions.
GO:0005141 interleukin-10 receptor binding
IEA
GO_REF:0000107 		ACCEPT
Summary: IEA transfer from rat Il10 (P29456). IL-10 receptor binding is the primary molecular function through which IL-10 initiates signaling.
Reason: IL-10 receptor binding is a core molecular function. IL-10 binds the IL-10RA/IL-10RB receptor complex to initiate downstream JAK-STAT signaling (UniProt P22301, deep research review).
GO:0008285 negative regulation of cell population proliferation
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: IEA transfer from mouse Il10 (P18893). IL-10 can inhibit proliferation of certain cell types including T cells and some other cell populations.
Reason: IL-10 can inhibit T cell proliferation (PMID:8499633) and has anti-proliferative effects on some cell types, but this is a broad term that does not capture the specific immune regulatory context. Acceptable as a non-core annotation.
Supporting Evidence:
PMID:8499633
Human interleukin-10 (IL-10) inhibits T-cell proliferation and cytokine production in the presence of monocytes.
GO:0009410 response to xenobiotic stimulus
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: IEA transfer from rat Il10 (P29456). IL-10 expression may be induced by xenobiotic stimuli in rats, but this is not a core function for human IL-10.
Reason: Response to xenobiotic stimulus is a peripheral observation likely from rodent studies where IL-10 expression was measured after xenobiotic exposure. This does not represent a core function of IL-10 as a cytokine and is an over-annotation from ortholog transfer.
GO:0014823 response to activity
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: IEA transfer from rat Il10 (P29456). IL-10 levels may change with physical activity in rats, but this is not a core function.
Reason: Response to activity (physical exercise) is a peripheral observation. IL-10 levels may change as part of general immune modulation during exercise, but this does not represent a core function of the cytokine itself.
GO:0014854 response to inactivity
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: IEA transfer from rat Il10 (P29456). Similar to response to activity, this is a peripheral observation.
Reason: Response to inactivity is a peripheral observation from rodent studies. Not a core function of IL-10 as an anti-inflammatory cytokine.
GO:0032496 response to lipopolysaccharide
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: IEA transfer from rat Il10 (P29456). IL-10 is induced by LPS and also modulates the response to LPS.
Reason: IL-10 is both induced by LPS stimulation and acts to suppress LPS-induced inflammatory responses. This is a well-established aspect of IL-10 biology (PMID:14971032, PMID:10443688), though it represents a stimulus-response context rather than core function per se.
GO:0032720 negative regulation of tumor necrosis factor production
IEA
GO_REF:0000120 		ACCEPT
Summary: IEA annotation for negative regulation of TNF production. IL-10 is a potent suppressor of TNF production by monocytes/macrophages.
Reason: Suppression of TNF production was one of the earliest identified functions of IL-10 (PMID:1940799) and is a core anti-inflammatory activity. The TAS annotation from PMID:19262501 also supports this. This IEA annotation is correct.
GO:0032868 response to insulin
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: IEA transfer from rat Il10 (P29456). IL-10 levels may be affected by insulin in metabolic contexts.
Reason: Response to insulin is a peripheral metabolic observation from rodent studies. While there are links between IL-10 and metabolic regulation, this is not a core function of IL-10 as an immune cytokine.
GO:0034115 negative regulation of heterotypic cell-cell adhesion
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: IEA transfer from mouse Il10 (P18893). IL-10 can downregulate adhesion molecules such as ICAM-1 on monocytes.
Reason: IL-10 downregulates ICAM-1 and other adhesion molecules on monocytes (PMID:7512027 per UniProt), which affects cell-cell adhesion. This is a downstream consequence of IL-10's anti-inflammatory program rather than a core function, but it is a real effect.
GO:0034465 response to carbon monoxide
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: IEA transfer from rat Il10 (P29456). IL-10 expression may be induced by carbon monoxide in rat models.
Reason: Response to carbon monoxide is a highly peripheral observation from rodent studies. This is not a core function of IL-10 and represents an over-annotation via ortholog transfer.
GO:0043032 positive regulation of macrophage activation
IEA
GO_REF:0000107 		UNDECIDED
Summary: IEA transfer from rat Il10 (P29456). This seems contradictory since IL-10 is primarily known to suppress macrophage activation, not promote it.
Reason: IL-10 is primarily known as an inhibitor of macrophage activation (suppressing pro-inflammatory cytokine production and MHC class II expression). While IL-10 can have some activating effects on macrophages (e.g., promoting alternative/M2 activation), the annotation of "positive regulation of macrophage activation" without qualification is potentially misleading. The underlying rodent evidence is not accessible to verify.
GO:0043066 negative regulation of apoptotic process
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: IEA transfer from rat Il10 (P29456). IL-10 can inhibit apoptosis in certain cell types.
Reason: IL-10 has been shown to inhibit apoptosis in T cells starved of IL-2 (PMID:8312229) and can promote survival of certain immune cell types. This is a real but non-core effect of IL-10 signaling.
Supporting Evidence:
PMID:8312229
IL-10 inhibits apoptotic cell death in human T cells starved of IL-2.
GO:0043524 negative regulation of neuron apoptotic process
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: IEA transfer from rat Il10 (P29456). IL-10 has been reported to have neuroprotective effects in certain rodent models.
Reason: Neuroprotective effects of IL-10 have been observed in rodent models of neuroinflammation, but this is a highly context-dependent downstream effect rather than a core function of this immune cytokine. Over-annotation via ortholog transfer.
GO:0045019 negative regulation of nitric oxide biosynthetic process
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: IEA transfer from rat Il10 (P29456). IL-10 suppresses iNOS expression and NO production in activated macrophages.
Reason: IL-10 suppresses iNOS expression and nitric oxide production as part of its anti-inflammatory program in macrophages. This is a documented downstream effect of IL-10-mediated suppression of inflammatory gene expression, though not a core molecular function.
GO:0045787 positive regulation of cell cycle
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: IEA transfer from mouse Il10 (P18893). IL-10 can promote cell cycle progression in certain cell types.
Reason: While IL-10 can promote proliferation of certain cell types (e.g., B cells, mast cells), a generic "positive regulation of cell cycle" annotation is over-broad and does not capture the specific immune context. This is an over-annotation.
GO:0045944 positive regulation of transcription by RNA polymerase II
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: IEA transfer from mouse Il10 (P18893). IL-10 signaling leads to STAT3-dependent transcriptional activation of anti-inflammatory genes.
Reason: IL-10 does activate transcription of specific genes via STAT3, but this is an extremely broad GO term. It is technically correct as a downstream effect of IL-10 signaling but not informative about IL-10's specific function.
GO:0050807 regulation of synapse organization
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: IEA transfer from rat Il10 (P29456). IL-10 has been implicated in neuroimmune contexts.
Reason: Regulation of synapse organization is a very peripheral observation from rodent neuroimmune studies. This is not a core function of IL-10 as an immune cytokine and represents an over-annotation via ortholog transfer.
GO:0051384 response to glucocorticoid
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: IEA transfer from rat Il10 (P29456). Glucocorticoids can regulate IL-10 expression.
Reason: IL-10 expression is known to be regulated by glucocorticoids (also supported by IDA annotation from PMID:10443688). While this describes regulation of IL-10 rather than a function of IL-10, the annotation is not wrong per se. Keep as non-core.
GO:0071392 cellular response to estradiol stimulus
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: IEA transfer from rat Il10 (P29456). IL-10 levels may respond to estradiol in rodent studies.
Reason: Response to estradiol is a peripheral hormonal regulation observation from rodent studies. Not a core function of IL-10.
GO:0097421 liver regeneration
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: IEA transfer from rat Il10 (P29456). IL-10 may play a role in liver regeneration in rodent models.
Reason: Liver regeneration is a highly tissue-specific and peripheral observation. While IL-10 may be expressed during liver regeneration, this is not a core function of this immune cytokine.
GO:1903034 regulation of response to wounding
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: IEA transfer from mouse Il10 (P18893). IL-10 modulates wound healing by regulating inflammatory responses.
Reason: IL-10 does modulate wound healing through its anti-inflammatory properties, which is an extension of its core immune regulatory function. Keep as non-core since it is a contextual application of the core function.
GO:1903377 negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: IEA transfer from mouse Il10 (P18893). Highly specific neuroprotective annotation from rodent models.
Reason: This is an extremely specific neuroprotective annotation from mouse studies. IL-10 is not a neuron-specific factor; this represents a highly contextual observation from specific experimental paradigms that does not reflect a core function.
GO:1903672 positive regulation of sprouting angiogenesis
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: IEA transfer from mouse Il10 (P18893). IL-10 has been implicated in angiogenesis regulation.
Reason: Regulation of angiogenesis is a downstream pleiotropic effect rather than a core function of IL-10 as an immune cytokine. Over-annotation from ortholog transfer.
GO:1904706 negative regulation of vascular associated smooth muscle cell proliferation
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: IEA transfer from mouse Il10 (P18893). IL-10 may inhibit vascular smooth muscle cell proliferation.
Reason: Vascular smooth muscle cell proliferation regulation is a peripheral non-immune effect. Over-annotation from ortholog transfer.
GO:0045944 positive regulation of transcription by RNA polymerase II
IDA
PMID:7749983
Cross-linking of OX40 ligand, a member of the TNF/NGF cytoki... 		KEEP AS NON CORE
Summary: IDA annotation from PMID:7749983. This paper is about OX40L (TNFSF4), not about IL-10, so the reference is misattributed. However, IL-10 signaling through STAT3 does activate transcription of target genes, so the annotation itself is not wrong -- it is just a very broad term. Consistent with the IEA annotation for the same term which is marked KEEP_AS_NON_CORE.
Reason: The reference PMID:7749983 is misattributed (it describes OX40L cross-linking on murine B cells, not IL-10). Nevertheless, IL-10 does positively regulate transcription by RNA polymerase II via STAT3 signaling (PMID:16982608), so the annotation is biologically correct though overly broad. This is consistent with the IEA annotation for the same GO term. Kept as non-core because the term does not capture IL-10's specific function.
Supporting Evidence:
PMID:7749983
OX40 is a member of the TNF/NGF-receptor family expressed on activated T cells, whose ligand is found on activated T and B cells
GO:0140105 interleukin-10-mediated signaling pathway
IDA
PMID:7749983
Cross-linking of OX40 ligand, a member of the TNF/NGF cytoki... 		ACCEPT
Summary: IDA annotation from PMID:7749983. The reference is misattributed (paper is about OX40L/TNFSF4, not IL-10). However, IL-10 is the defining ligand for the IL-10-mediated signaling pathway, so the annotation itself is correct and well-supported by IBA, IDA from PMID:10443688, and IDA from PMID:24994464.
Reason: IL-10 is the defining ligand for the IL-10-mediated signaling pathway; this is a core function that is essentially tautological. The reference PMID:7749983 is misattributed (it describes OX40L cross-linking on murine B cells), but the annotation is strongly supported by multiple other evidence lines including IBA (GO_REF:0000033), IDA (PMID:10443688), and IDA (PMID:24994464). Accepting the annotation despite the reference error because the biology is unambiguous.
Supporting Evidence:
PMID:7749983
OX40 is a member of the TNF/NGF-receptor family expressed on activated T cells, whose ligand is found on activated T and B cells
GO:0140105 interleukin-10-mediated signaling pathway
IDA
PMID:10443688
Tumor necrosis factor alpha decreases, and interleukin-10 in... 		ACCEPT
Summary: IDA annotation for IL-10-mediated signaling pathway from PMID:10443688. This publication is not available for review but is frequently cited for IL-10 annotations and is likely a primary study of IL-10 signaling.
Reason: IL-10 is the defining ligand for the IL-10-mediated signaling pathway. This PMID is cited for multiple IL-10 annotations and appears to be a key primary study. The annotation is consistent with the known biology of IL-10.
Supporting Evidence:
PMID:10443688
interleukin (IL)-10 (an anti-inflammatory cytokine) to differentially regulate the sensitivity of human monocytes/macrophages to glucocorticoids.
GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT
IDA
PMID:16982608
Conformational changes mediate interleukin-10 receptor 2 (IL... 		ACCEPT
Summary: IDA annotation for positive regulation of JAK-STAT signaling from PMID:16982608. This paper likely describes the structural basis of IL-10 signaling through its receptor complex to activate JAK1/TYK2/STAT3.
Reason: This is a core aspect of IL-10 function. IL-10 engagement of IL-10RA/IL-10RB activates JAK1 and TYK2, leading to STAT3 phosphorylation. PMID:16982608 is cited multiple times for IL-10 receptor and signaling annotations, suggesting it is a key structural/functional study (deep research review).
Supporting Evidence:
PMID:16982608
The ternary IL-10 signaling complex is assembled in a sequential order with the IL-10.IL-10R1 interaction occurring first followed by engagement of the IL-10R2 chain.
GO:0050864 regulation of B cell activation
IDA
PMID:35443184
Human IL-10-producing B cells have diverse states that are i... 		KEEP AS NON CORE
Summary: IDA annotation for regulation of B cell activation from PMID:35443184. IL-10 has well-established effects on B cells.
Reason: IL-10 regulates B cell activation, which is a real but non-core function relative to its primary anti-inflammatory role. IL-10 was originally characterized as a B cell growth factor as well as a cytokine synthesis inhibitor (PMID:9184696, deep research review). Keep as non-core.
Supporting Evidence:
PMID:35443184
Regulatory B cells (Bregs) suppress immune responses through the secretion of interleukin-10 (IL-10). This immunomodulatory capacity holds therapeutic potential, yet a definitional immunophenotype for enumeration and prospective isolation of B cells capable of IL-10 production remains elusive.
GO:0005125 cytokine activity
IDA
PMID:24994464
Low IL10 serum levels as key factor for predicting the susta... 		ACCEPT
Summary: IDA annotation for cytokine activity from PMID:24994464 (about IL10 serum levels in HCV patients). This confirms IL-10 functions as a circulating cytokine.
Reason: Cytokine activity is the core molecular function of IL-10. Multiple lines of evidence support this (PMID:1940799, PMID:24994464, IBA, IEA).
Supporting Evidence:
PMID:24994464
the levels of IL10 seem to influence response to IFNα/RIB therapy.
GO:0005615 extracellular space
IDA
PMID:24994464
Low IL10 serum levels as key factor for predicting the susta... 		ACCEPT
Summary: IDA for extracellular space from PMID:24994464 (IL10 serum levels).
Reason: IL-10 is a secreted cytokine detected in serum/plasma. Extracellular space localization is well-established.
Supporting Evidence:
PMID:24994464
IL10 serum levels could be further explored as a useful algorithm for identify the CT/TT SVR patients.
GO:0140105 interleukin-10-mediated signaling pathway
IDA
PMID:24994464
Low IL10 serum levels as key factor for predicting the susta... 		ACCEPT
Summary: IDA for IL-10-mediated signaling pathway from PMID:24994464.
Reason: IL-10 is the defining ligand for IL-10-mediated signaling. This is a core annotation well-supported by multiple evidence lines.
Supporting Evidence:
PMID:24994464
the levels of IL10 seem to influence response to IFNα/RIB therapy.
GO:0071222 cellular response to lipopolysaccharide
IDA
PMID:23071313
IL-10-induced microRNA-187 negatively regulates TNF-α, IL-6,... 		KEEP AS NON CORE
Summary: IDA annotation for cellular response to LPS from PMID:23071313. IL-10 is both induced by and modulates the cellular response to LPS.
Reason: IL-10 modulates the cellular response to LPS by suppressing pro-inflammatory cytokine production. This is a well-established aspect of IL-10 biology but represents a specific stimulus-response context rather than core function.
Supporting Evidence:
PMID:23071313
IL-10 is a potent anti-inflammatory molecule that, in phagocytes, negatively targets cytokine expression at transcriptional and posttranscriptional levels.
GO:1902895 positive regulation of miRNA transcription
IDA
PMID:23071313
IL-10-induced microRNA-187 negatively regulates TNF-α, IL-6,... 		KEEP AS NON CORE
Summary: IDA annotation for positive regulation of miRNA transcription from PMID:23071313. IL-10 has been shown to regulate miRNA expression as part of its signaling.
Reason: IL-10 signaling through STAT3 can regulate miRNA transcription as a downstream effect. This is a mechanistic detail of IL-10 signaling rather than a core function, but it is experimentally supported. Keep as non-core.
Supporting Evidence:
PMID:23071313
we identify miR-187 as an IL-10-dependent miRNA playing a role in IL-10-mediated suppression of TNF-α, IL-6, and the p40 subunit of IL-12 (IL-12p40) produced by primary human monocytes following activation of Toll-like receptor 4 (TLR4).
GO:0050728 negative regulation of inflammatory response
IDA
PMID:10443688
Tumor necrosis factor alpha decreases, and interleukin-10 in... 		ACCEPT
Summary: IDA annotation for negative regulation of inflammatory response from PMID:10443688. This is a core function of IL-10.
Reason: This is the single most important function of IL-10. The anti-inflammatory activity of IL-10 has been demonstrated in numerous experimental systems (PMID:1940799, PMID:10443688, deep research review).
Supporting Evidence:
PMID:10443688
IL-10 acts synergistically with glucocorticoids. This is accompanied by opposite glucocorticoid receptor changes, respectively opposing and favoring glucocorticoid actions.
GO:0001818 negative regulation of cytokine production
IDA
PMID:1940799
Interleukin 10(IL-10) inhibits cytokine synthesis by human m... 		ACCEPT
Summary: IDA annotation for negative regulation of cytokine production from PMID:1940799. This is the seminal paper by de Waal Malefyt et al. (1991) establishing IL-10 as a cytokine synthesis inhibitor.
Reason: This is one of the most fundamental annotations for IL-10. PMID:1940799 demonstrated that IL-10 inhibits cytokine synthesis by human monocytes. IL-10 was originally named Cytokine Synthesis Inhibitory Factor (CSIF) based on this activity.
Supporting Evidence:
PMID:1940799
Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes.
GO:0010507 negative regulation of autophagy
IDA
PMID:26962683
IL10 inhibits starvation-induced autophagy in hypertrophic s... 		KEEP AS NON CORE
Summary: IDA annotation for negative regulation of autophagy from PMID:26962683, which showed IL-10 inhibits starvation-induced autophagy in hypertrophic scar fibroblasts via STAT3/AKT-mTOR signaling crosstalk.
Reason: IL-10 has been shown to inhibit autophagy in hypertrophic scar fibroblasts via crosstalk between IL10-IL10R-STAT3 and IL10-AKT-mTOR pathways (PMID:26962683). This is a real but highly context-specific effect, not a core function of IL-10.
Supporting Evidence:
PMID:26962683
IL10 inhibits starvation-induced autophagy in hypertrophic scar fibroblasts via cross talk between the IL10-IL10R-STAT3 and IL10-AKT-mTOR pathways.
GO:0045347 negative regulation of MHC class II biosynthetic process
IDA
PMID:1940799
Interleukin 10(IL-10) inhibits cytokine synthesis by human m... 		ACCEPT
Summary: IDA annotation for negative regulation of MHC class II biosynthetic process from PMID:1940799. IL-10 downregulates MHC class II expression on monocytes.
Reason: IL-10 downregulation of MHC class II expression on monocytes and macrophages is a core function directly related to its immune suppressive activity (PMID:1940799, PMID:8144879 per UniProt, deep research review).
Supporting Evidence:
PMID:1940799
Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes.
GO:0046983 protein dimerization activity
IDA
PMID:16982608
Conformational changes mediate interleukin-10 receptor 2 (IL... 		ACCEPT
Summary: IDA annotation for protein dimerization activity from PMID:16982608. IL-10 functions as a homodimer.
Reason: IL-10 forms a non-covalent homodimer as its biologically active form. The dimer is stabilized by domain swapping and intrachain disulfide bonds. This is well-established from crystal structures and biochemical studies (UniProt P22301, PMID:8364028, deep research review).
Supporting Evidence:
PMID:16982608
These studies highlight the importance of structure in regulating low affinity protein-protein interactions and IL-10 signal transduction.
GO:0045893 positive regulation of DNA-templated transcription
IDA
PMID:16606666
B7-H4 expression identifies a novel suppressive macrophage p... 		KEEP AS NON CORE
Summary: IDA annotation for positive regulation of transcription from PMID:16606666. IL-10 signaling through STAT3 activates transcription of target genes.
Reason: IL-10 does activate transcription via STAT3 signaling. This is technically correct but is a very broad term. The specific transcriptional effects (anti-inflammatory gene induction) are better captured by other annotations. Keep as non-core.
Supporting Evidence:
PMID:16606666
Interleukin (IL)-6 and IL-10 are found in high concentrations in the tumor microenvironment. These cytokines stimulate macrophage B7-H4 expression.
GO:0045893 positive regulation of DNA-templated transcription
IMP
PMID:17875732
Relationship between B7-H4, regulatory T cells, and patient ... 		KEEP AS NON CORE
Summary: IMP annotation for positive regulation of transcription from PMID:17875732. This paper showed that tumor Treg cells enable macrophages to produce IL-10 and IL-6, and that tumor macrophages stimulate B7-H4 expression in an autocrine manner through IL-10 and IL-6. IL-10 thus indirectly promotes transcription of B7-H4 in this tumor microenvironment context.
Reason: PMID:17875732 demonstrates that IL-10 (produced by Treg-stimulated macrophages) stimulates B7-H4 expression on macrophages in ovarian carcinoma, which constitutes positive regulation of transcription. This is consistent with IL-10's known ability to activate STAT3-dependent gene transcription and with the IDA annotation for the same term (GO:0045893) from PMID:16606666, which is also marked KEEP_AS_NON_CORE. The transcriptional regulation is a downstream consequence of IL-10 signaling rather than a core function.
Supporting Evidence:
PMID:17875732
Tumor Treg cells enabled macrophages to spontaneously produce interleukin (IL)-10 and IL-6. Tumor macrophages stimulated B7-H4 expression in an autocrine manner through IL-10 and IL-6.
GO:0007259 cell surface receptor signaling pathway via JAK-STAT
NAS
PMID:33737461
Structure-based decoupling of the pro- and anti-inflammatory... 		ACCEPT
Summary: NAS annotation for JAK-STAT signaling from PMID:33737461 (ComplexPortal). IL-10 signals through its receptor complex to activate JAK-STAT signaling.
Reason: IL-10 signaling through JAK1/TYK2/STAT3 is a core pathway. This NAS annotation from ComplexPortal is consistent with the well-established signaling mechanism (deep research review).
Supporting Evidence:
PMID:33737461
We used a structure-based approach to deconvolute IL-10 pleiotropy by determining the structure of the IL-10 receptor (IL-10R) complex by cryo-electron microscopy at a resolution of 3.5 angstroms.
GO:0008284 positive regulation of cell population proliferation
NAS
PMID:31611251
Biology and therapeutic potential of interleukin-10. 		KEEP AS NON CORE
Summary: NAS annotation for positive regulation of cell proliferation from PMID:31611251 (ComplexPortal).
Reason: IL-10 can promote proliferation of certain cell types, particularly B cells and mast cells. However, it also inhibits proliferation of other cell types (T cells). This is a context-dependent effect, keep as non-core.
Supporting Evidence:
PMID:31611251
IL-10 (Fiorentino et al., 1989; Moore et al., 1990) is the founding member of a family of cytokines that also includes IL-19, IL-20, IL-22, IL-24, IL-26, IL-28A, IL-28B, and IL-29
GO:0019221 cytokine-mediated signaling pathway
NAS
PMID:33737461
Structure-based decoupling of the pro- and anti-inflammatory... 		ACCEPT
Summary: NAS annotation for cytokine-mediated signaling pathway from ComplexPortal.
Reason: IL-10 is a cytokine that mediates signaling through its receptor. This is a core annotation that is well-supported (deep research review).
Supporting Evidence:
PMID:33737461
Interleukin-10 (IL-10) is an immunoregulatory cytokine with both anti-inflammatory and immunostimulatory properties and is frequently dysregulated in disease.
GO:0042531 positive regulation of tyrosine phosphorylation of STAT protein
NAS
PMID:16982608
Conformational changes mediate interleukin-10 receptor 2 (IL... 		ACCEPT
Summary: NAS annotation for positive regulation of STAT tyrosine phosphorylation from PMID:16982608.
Reason: IL-10 signaling leads to JAK1/TYK2-mediated tyrosine phosphorylation of STAT3, which is the canonical downstream signaling event. This is a core mechanistic annotation (PMID:16982608, deep research review).
Supporting Evidence:
PMID:16982608
The basic mechanistic features of the assembly process are likely shared by six additional class-2 cytokines (viral IL-10s, IL-22, IL-26, IL-28A, IL28B, and IL-29) to promote IL-10R2 binding to six additional receptor complexes.
GO:0050728 negative regulation of inflammatory response
NAS
PMID:31611251
Biology and therapeutic potential of interleukin-10. 		ACCEPT
Summary: NAS annotation for negative regulation of inflammatory response from ComplexPortal.
Reason: Anti-inflammatory activity is the core function of IL-10. Multiple evidence codes support this annotation (IBA, IDA, NAS from multiple sources).
Supporting Evidence:
PMID:31611251
The cytokine IL-10 is a key anti-inflammatory mediator ensuring protection of a host from over-exuberant responses to pathogens and microbiota
GO:0050728 negative regulation of inflammatory response
NAS
PMID:21857966
WNT5A signaling contributes to Aβ-induced neuroinflammation ... 		ACCEPT
Summary: NAS annotation for negative regulation of inflammatory response from PMID:21857966, which is about WNT5A signaling and neuroinflammation.
Reason: While PMID:21857966 is primarily about WNT5A, IL-10 is mentioned as an anti-inflammatory cytokine in the context of neuroinflammation. The annotation itself is correct regardless of the reference context.
Supporting Evidence:
PMID:21857966
We found that IL-10, a prototypic anti-inflammatory cytokine, caused concentration-dependent rescue effects on Aβ toxicity
GO:0034115 negative regulation of heterotypic cell-cell adhesion
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: ISS annotation transferred from mouse Il10 (P18893) for negative regulation of heterotypic cell-cell adhesion. IL-10 downregulates adhesion molecules.
Reason: IL-10 downregulates ICAM-1 and other adhesion molecules on monocytes (PMID:7512027 per UniProt), which affects cell-cell adhesion. Transfer from mouse Il10 is reasonable. Keep as non-core.
GO:0034116 positive regulation of heterotypic cell-cell adhesion
ISS
GO_REF:0000024 		REMOVE
Summary: ISS annotation transferred from FasL/TNFSF6 (P06804) for positive regulation of heterotypic cell-cell adhesion. This is an inappropriate transfer.
Reason: This annotation was transferred from FasL (TNFSF6, P06804), which is a death ligand in the TNF superfamily. IL-10 is an anti-inflammatory cytokine in the IL-10 family. These proteins are functionally very different and the transfer is inappropriate. FasL mediates apoptotic and adhesion effects through completely different mechanisms than IL-10.
GO:0045930 negative regulation of mitotic cell cycle
ISS
GO_REF:0000024 		REMOVE
Summary: ISS annotation transferred from FasL/TNFSF6 (P06804). Inappropriate transfer.
Reason: Transfer from FasL (P06804) is inappropriate. FasL-mediated cell cycle arrest is related to its death receptor signaling, which has no mechanistic parallel in IL-10 biology.
GO:0072577 endothelial cell apoptotic process
ISS
GO_REF:0000024 		REMOVE
Summary: ISS annotation transferred from FasL/TNFSF6 (P06804). Inappropriate transfer.
Reason: Transfer from FasL (P06804) is inappropriate. FasL induces apoptosis through Fas receptor engagement, which is mechanistically unrelated to IL-10 function. IL-10 is generally anti-apoptotic, not pro-apoptotic.
GO:1904706 negative regulation of vascular associated smooth muscle cell proliferation
ISS
GO_REF:0000024 		MARK AS OVER ANNOTATED
Summary: ISS annotation transferred from mouse Il10 (P18893). IL-10 may inhibit vascular smooth muscle cell proliferation.
Reason: Transfer from mouse Il10 (P18893) is reasonable in principle, but regulation of vascular smooth muscle cell proliferation is a peripheral non-immune effect. Over-annotation for this immune cytokine.
GO:1904707 positive regulation of vascular associated smooth muscle cell proliferation
ISS
GO_REF:0000024 		REMOVE
Summary: ISS annotation transferred from FasL/TNFSF6 (P06804). Inappropriate transfer.
Reason: Transfer from FasL (P06804) is inappropriate. The functional mechanisms of FasL and IL-10 are completely different, and the vascular smooth muscle proliferation effects of FasL cannot be transferred to IL-10.
GO:0008285 negative regulation of cell population proliferation
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: ISS annotation transferred from mouse Il10 (P18893). IL-10 can inhibit proliferation of certain cell types.
Reason: IL-10 can inhibit T cell proliferation (PMID:8499633) and has anti-proliferative effects on certain cell types. Transfer from mouse Il10 is reasonable. Keep as non-core.
GO:1903034 regulation of response to wounding
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: ISS annotation transferred from mouse Il10 (P18893). IL-10 modulates wound healing through anti-inflammatory effects.
Reason: IL-10 modulates wound healing responses through its anti-inflammatory properties. Transfer from mouse Il10 is reasonable. Keep as non-core.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-449803 		ACCEPT
Summary: TAS annotation for extracellular region from Reactome (IL10 dimer binds IL10RA:JAK1). IL-10 is a secreted protein.
Reason: IL-10 is secreted and localizes to the extracellular region where it binds its receptor complex. Reactome pathway annotation is consistent with known biology.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-449811 		ACCEPT
Summary: TAS for extracellular region from Reactome (IL10 dimer:2xIL10RA1:JAK1 binds IL10RB:TYK2).
Reason: Same as above. IL-10 is extracellular. Reactome annotation consistent with known biology.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-449855 		ACCEPT
Summary: TAS for extracellular region from Reactome (IL10 dimerizes).
Reason: IL-10 dimerizes in the extracellular space. Correct annotation.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-6784006 		ACCEPT
Summary: TAS for extracellular region from Reactome (STAT3 phosphorylation by JAK1/TYK2).
Reason: IL-10 is the extracellular ligand in this signaling event. Correct.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-6784319 		ACCEPT
Summary: TAS for extracellular region from Reactome (JAK1,TYK2 phosphorylation).
Reason: IL-10 is extracellular during this signaling step. Correct.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-6784323 		ACCEPT
Summary: TAS for extracellular region from Reactome (receptor complex binds STAT3).
Reason: IL-10 remains in the extracellular region bound to its receptor. Correct.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-6784324 		ACCEPT
Summary: TAS for extracellular region from Reactome (IL10RA phosphorylation).
Reason: IL-10 is extracellular in this signaling context. Correct.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-6784791 		ACCEPT
Summary: TAS for extracellular region from Reactome (STAT3 dissociation from receptor).
Reason: IL-10 is extracellular. Correct.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-6789615 		ACCEPT
Summary: TAS for extracellular region from Reactome (STAT3-upregulated extracellular protein expression).
Reason: IL-10 is extracellular. Correct.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-8981073 		ACCEPT
Summary: TAS for extracellular region from Reactome (Expression of Interleukin-10).
Reason: IL-10 is expressed and secreted to the extracellular region. Correct.
GO:0005576 extracellular region
TAS
Reactome:R-HSA-9664346 		ACCEPT
Summary: TAS for extracellular region from Reactome (IL10 gene produces IL10 protein).
Reason: IL-10 is a secreted extracellular protein. Correct.
GO:0005615 extracellular space
IDA
PMID:21323571
Pro/anti-inflammatory cytokines in the pathogenesis of prema... 		ACCEPT
Summary: IDA for extracellular space from PMID:21323571, which studied cytokines in premature coronary artery disease patients.
Reason: IL-10 is detected in the extracellular space (serum/plasma) of patients. Consistent with IL-10 being a secreted cytokine.
Supporting Evidence:
PMID:21323571
Serum IL-10, IL-18, and TNF-alpha were measured using enzyme-linked immunosorbent assay
GO:0032692 negative regulation of interleukin-1 production
TAS
PMID:19262501
A novel regulatory B-cell population in sheep Peyer's patche... 		ACCEPT
Summary: TAS annotation for negative regulation of IL-1 production from PMID:19262501, about regulatory B cells in sheep Peyer's patches that secrete IL-10 and downregulate TLR9-induced cytokine responses.
Reason: IL-10 inhibition of IL-1 production is well-established as part of its core anti-inflammatory function. The original CSIF description (PMID:1940799) showed IL-10 inhibits multiple pro-inflammatory cytokines. PMID:19262501 provides additional evidence from Peyer's patch B cells.
Supporting Evidence:
PMID:19262501
A novel regulatory B-cell population in sheep Peyer's patches spontaneously secretes IL-10 and downregulates TLR9-induced IFNalpha responses.
GO:0032695 negative regulation of interleukin-12 production
TAS
PMID:19262501
A novel regulatory B-cell population in sheep Peyer's patche... 		ACCEPT
Summary: TAS for negative regulation of IL-12 production from PMID:19262501.
Reason: IL-10 inhibition of IL-12 production by monocytes/macrophages and dendritic cells is one of its most important anti-inflammatory activities. IL-12 suppression is critical for limiting Th1 responses (PMID:19262501, deep research review).
Supporting Evidence:
PMID:19262501
Neutralization of the IL-10 or depletion of CD21(+) B cells resulted in a significant increase in CpG-induced IFNalpha-response in PPs, suggesting that IL-10 from B cells regulate innate responses in PPs.
GO:0032701 negative regulation of interleukin-18 production
TAS
PMID:19262501
A novel regulatory B-cell population in sheep Peyer's patche... 		ACCEPT
Summary: TAS for negative regulation of IL-18 production from PMID:19262501.
Reason: IL-10 suppression of IL-18 production is consistent with its broad anti-inflammatory activity. IL-18 is a pro-inflammatory cytokine that IL-10 is known to suppress (PMID:19262501).
Supporting Evidence:
PMID:19262501
PP cells spontaneously secreted high levels of IL-10, and the primary source of the IL-10 was resting CD5(-)CD11c(-)CD21(+) B cells.
GO:0032715 negative regulation of interleukin-6 production
TAS
PMID:19262501
A novel regulatory B-cell population in sheep Peyer's patche... 		ACCEPT
Summary: TAS for negative regulation of IL-6 production from PMID:19262501.
Reason: IL-10 inhibition of IL-6 production is well-established and also supported by IDA annotation from PMID:10443688 (PMID:19262501).
Supporting Evidence:
PMID:19262501
PP cells spontaneously secreted high levels of IL-10, and the primary source of the IL-10 was resting CD5(-)CD11c(-)CD21(+) B cells.
GO:0032717 negative regulation of interleukin-8 production
TAS
PMID:19262501
A novel regulatory B-cell population in sheep Peyer's patche... 		ACCEPT
Summary: TAS for negative regulation of IL-8 production from PMID:19262501.
Reason: IL-10 inhibition of IL-8 (CXCL8) production is part of its broad suppression of pro-inflammatory mediators (PMID:19262501).
Supporting Evidence:
PMID:19262501
PP cells spontaneously secreted high levels of IL-10, and the primary source of the IL-10 was resting CD5(-)CD11c(-)CD21(+) B cells.
GO:0032720 negative regulation of tumor necrosis factor production
TAS
PMID:19262501
A novel regulatory B-cell population in sheep Peyer's patche... 		ACCEPT
Summary: TAS for negative regulation of TNF production from PMID:19262501.
Reason: IL-10 suppression of TNF production is one of the earliest and best characterized functions of IL-10 (PMID:1940799, PMID:19262501).
Supporting Evidence:
PMID:19262501
A novel regulatory B-cell population in sheep Peyer's patches spontaneously secretes IL-10 and downregulates TLR9-induced IFNalpha responses.
GO:0071650 negative regulation of chemokine (C-C motif) ligand 5 production
TAS
PMID:19262501
A novel regulatory B-cell population in sheep Peyer's patche... 		ACCEPT
Summary: TAS for negative regulation of CCL5 (RANTES) production from PMID:19262501.
Reason: IL-10 suppression of chemokine production including CCL5/RANTES is consistent with its broad anti-inflammatory activity (PMID:19262501).
Supporting Evidence:
PMID:19262501
These IL-10-secreting PP B cells may represent a novel subset of the recently proposed regulatory B cells (B(regs)) in the intestine.
GO:1903659 regulation of complement-dependent cytotoxicity
IMP NOT
PMID:16034134
IL-4 and IL-13 induce protection of porcine endothelial cell... 		ACCEPT
Summary: NOT annotation: IL-10 does NOT regulate complement-dependent cytotoxicity based on PMID:16034134.
Reason: This is a NOT annotation indicating IL-10 was tested and found not to regulate complement-dependent cytotoxicity. Negative results are informative and should be retained.
Supporting Evidence:
PMID:16034134
porcine EC incubated with IL-4 or IL-13, but not with IL-10 or IL-11, became protected from killing by complement and apoptosis induced by TNF-alpha plus cycloheximide.
GO:2000352 negative regulation of endothelial cell apoptotic process
IMP NOT
PMID:16034134
IL-4 and IL-13 induce protection of porcine endothelial cell... 		ACCEPT
Summary: NOT annotation: IL-10 does NOT negatively regulate endothelial cell apoptotic process based on PMID:16034134.
Reason: This is a NOT annotation indicating IL-10 was tested and found not to inhibit endothelial cell apoptosis. Negative results are informative.
Supporting Evidence:
PMID:16034134
porcine EC incubated with IL-4 or IL-13, but not with IL-10 or IL-11, became protected from killing by complement and apoptosis induced by TNF-alpha plus cycloheximide.
GO:0042130 negative regulation of T cell proliferation
NAS
PMID:14971032
Interleukin 10 regulates cell surface and soluble LIR-2 (CD8... 		ACCEPT
Summary: NAS for negative regulation of T cell proliferation from PMID:14971032. IL-10 upregulates LIR-2 on DCs, causing T cell hyporesponsiveness.
Reason: IL-10 inhibition of T cell proliferation is well-documented. PMID:14971032 showed IL-10 regulates LIR-2 on dendritic cells resulting in T cell hyporesponsiveness. Also supported by PMID:8499633 which showed direct inhibition of T cell growth.
Supporting Evidence:
PMID:14971032
Interleukin 10 regulates cell surface and soluble LIR-2 (CD85d) expression on dendritic cells resulting in T cell hyporesponsiveness in vitro.
PMID:8499633
Human interleukin-10 (IL-10) inhibits T-cell proliferation and cytokine production in the presence of monocytes.
GO:0071222 cellular response to lipopolysaccharide
NAS
PMID:14971032
Interleukin 10 regulates cell surface and soluble LIR-2 (CD8... 		KEEP AS NON CORE
Summary: NAS for cellular response to LPS from PMID:14971032. IL-10 modulates the response to LPS.
Reason: IL-10 modulates the cellular response to LPS stimulation by suppressing pro-inflammatory cytokine production. This is a stimulus-response context for IL-10 function. Keep as non-core.
Supporting Evidence:
PMID:14971032
LPS-stimulated, LIR-2-transfected DC inhibited the proliferation of T cells in autologous, as well as allogeneic culture systems in vitro.
GO:0060302 negative regulation of cytokine activity
IMP
PMID:9847016
Human interleukin 10 suppresses production of inflammatory m... 		ACCEPT
Summary: IMP annotation for negative regulation of cytokine activity from PMID:9847016. IL-10 suppresses cytokine activity as part of its anti-inflammatory program.
Reason: IL-10 negatively regulates the activity of multiple pro-inflammatory cytokines. This is consistent with its core anti-inflammatory function.
Supporting Evidence:
PMID:9847016
Preincubation of LPS-stimulated peritoneal macrophages with rhuIL-10 caused significant (P<0.05) reduction in secretion of TNF, IL-6, and PGE2, in a dose-dependent manner.
GO:0002904 positive regulation of B cell apoptotic process
IDA
PMID:9184696
The apoptosis and proliferation of SAC-activated B cells by ... 		KEEP AS NON CORE
Summary: IDA for positive regulation of B cell apoptotic process from PMID:9184696. This paper showed dual effects of IL-10 on SAC-activated B cells: promoting apoptosis at the initiation of activation and proliferation after pre-activation.
Reason: PMID:9184696 demonstrated that IL-10 has dual effects on B cells depending on activation state. IL-10 induces apoptosis in B cells at early stages of activation while promoting survival/proliferation of pre-activated B cells. The pro-apoptotic effect is context-dependent and not a core function.
Supporting Evidence:
PMID:9184696
The apoptosis and proliferation of SAC-activated B cells by IL-10 are associated with changes in Bcl-2, Bcl-xL, and Mcl-1 expression.
GO:0010468 regulation of gene expression
IDA
PMID:9184696
The apoptosis and proliferation of SAC-activated B cells by ... 		KEEP AS NON CORE
Summary: IDA for regulation of gene expression from PMID:9184696. IL-10 treatment altered expression of Bcl-2, Bcl-xL, and Mcl-1 in B cells.
Reason: IL-10 does regulate gene expression through STAT3 signaling. This is a very broad term; the specific gene expression changes (Bcl-2 family members) are context-specific to the B cell activation study (PMID:9184696). Keep as non-core.
Supporting Evidence:
PMID:9184696
The apoptosis and proliferation of SAC-activated B cells by IL-10 are associated with changes in Bcl-2, Bcl-xL, and Mcl-1 expression.
GO:0030889 negative regulation of B cell proliferation
IDA
PMID:9184696
The apoptosis and proliferation of SAC-activated B cells by ... 		KEEP AS NON CORE
Summary: IDA for negative regulation of B cell proliferation from PMID:9184696. Context-dependent effect of IL-10 on B cell proliferation.
Reason: PMID:9184696 showed that IL-10 can inhibit B cell proliferation depending on the activation state of the B cells. This is a real but context-dependent effect. Keep as non-core.
Supporting Evidence:
PMID:9184696
The apoptosis and proliferation of SAC-activated B cells by IL-10 are associated with changes in Bcl-2, Bcl-xL, and Mcl-1 expression.
GO:0051045 negative regulation of membrane protein ectodomain proteolysis
IDA
PMID:18383040
Interleukin-10 regulates TNF-alpha-converting enzyme (TACE/A... 		KEEP AS NON CORE
Summary: IDA for negative regulation of membrane protein ectodomain proteolysis from PMID:18383040. IL-10 may inhibit shedding of certain membrane proteins.
Reason: PMID:18383040 showed IL-10 inhibits TACE/ADAM-17 activity on monocytes, which regulates TNF-alpha shedding. This is a downstream effect of IL-10 anti-inflammatory signaling. Keep as non-core.
Supporting Evidence:
PMID:18383040
In the presence of IL-10, TNF-alpha production and activation of surface TACE was significantly inhibited.
GO:0001819 positive regulation of cytokine production
IDA
PMID:10443688
Tumor necrosis factor alpha decreases, and interleukin-10 in... 		KEEP AS NON CORE
Summary: IDA for positive regulation of cytokine production from PMID:10443688. IL-10 can positively regulate production of certain cytokines while suppressing others.
Reason: While IL-10 is primarily known as an inhibitor of pro-inflammatory cytokines, it can promote production of certain cytokines (e.g., it can enhance IL-1RA production). This dual activity is consistent with IL-10 biology. Keep as non-core since the primary function is anti-inflammatory.
Supporting Evidence:
PMID:10443688
its effect on IL-10 secretion was biphasic, producing stimulation at lower, and inhibition at higher doses.
GO:0002719 negative regulation of cytokine production involved in immune response
IDA
PMID:10443688
Tumor necrosis factor alpha decreases, and interleukin-10 in... 		ACCEPT
Summary: IDA for negative regulation of cytokine production in immune response from PMID:10443688.
Reason: This is a core function of IL-10. It specifically captures the immune context of IL-10's cytokine-suppressive activity. More specific than the general negative regulation of cytokine production (GO:0001818) and directly relevant to IL-10's primary role.
Supporting Evidence:
PMID:10443688
Dexamethasone had different effects on LPS-induced TNFalpha and IL-10 secretion; whereas it suppressed TNFalpha in a dose-dependent fashion
GO:0005125 cytokine activity
NAS
PMID:10443688
Tumor necrosis factor alpha decreases, and interleukin-10 in... 		ACCEPT
Summary: NAS for cytokine activity from PMID:10443688. Redundant with IBA and IDA annotations.
Reason: Cytokine activity is the core molecular function. Multiple evidence codes support this annotation.
Supporting Evidence:
PMID:10443688
interleukin (IL)-10 (an anti-inflammatory cytokine)
GO:0005615 extracellular space
IDA
PMID:10443688
Tumor necrosis factor alpha decreases, and interleukin-10 in... 		ACCEPT
Summary: IDA for extracellular space from PMID:10443688.
Reason: IL-10 is secreted and found in the extracellular space. Well-established.
Supporting Evidence:
PMID:10443688
the sensitivity of these cells to glucocorticoids is altered by TNFalpha or IL-10 pretreatment
GO:0032715 negative regulation of interleukin-6 production
IDA
PMID:10443688
Tumor necrosis factor alpha decreases, and interleukin-10 in... 		ACCEPT
Summary: IDA for negative regulation of IL-6 production from PMID:10443688.
Reason: IL-10 suppression of IL-6 production is a well-characterized core anti-inflammatory activity. Also supported by TAS from PMID:19262501.
Supporting Evidence:
PMID:10443688
with IL-10 improved, the ability of dexamethasone to suppress IL-6 secretion in whole-blood cell cultures
GO:0051384 response to glucocorticoid
IDA
PMID:10443688
Tumor necrosis factor alpha decreases, and interleukin-10 in... 		KEEP AS NON CORE
Summary: IDA for response to glucocorticoid from PMID:10443688. IL-10 expression is regulated by glucocorticoids.
Reason: Glucocorticoid regulation of IL-10 expression is documented but describes regulation of IL-10 rather than a core function of IL-10 itself. Keep as non-core.
Supporting Evidence:
PMID:10443688
IL-10 increased (P < 0.001), the concentration of dexamethasone binding sites in these cells
GO:0002237 response to molecule of bacterial origin
IDA
PMID:17449476
Eis (enhanced intracellular survival) protein of Mycobacteri... 		KEEP AS NON CORE
Summary: IDA for response to molecule of bacterial origin from PMID:17449476. IL-10 is produced in response to bacterial products.
Reason: IL-10 production is induced by bacterial products as part of the immune response regulatory feedback loop. This describes a context for IL-10 induction rather than a core function. Keep as non-core.
Supporting Evidence:
PMID:17449476
there is increased production of interferon-gamma and interleukin-10, which indicates that immunity in response to Eis treatment is skewed away from a protective T(H)1 response
GO:0030595 leukocyte chemotaxis
TAS
PMID:9405662
Identification of functional domains on human interleukin 10 		KEEP AS NON CORE
Summary: TAS for leukocyte chemotaxis from PMID:9405662. This paper identified functional domains on human IL-10 (also referenced for protein sequence in UniProt).
Reason: IL-10 can modulate leukocyte chemotaxis through its effects on chemokine production and adhesion molecule expression. PMID:9405662 studied functional domains of IL-10 including chemotactic effects. Keep as non-core.
Supporting Evidence:
PMID:9405662
IL-10 significantly affects chemokine biology, because human IL-10 inhibits chemokine production and is a specific chemotactic factor for CD8+ T cells.
GO:0030183 B cell differentiation
NAS
PMID:8228801
Interleukin 10 (IL-10) upregulates functional high affinity ... 		KEEP AS NON CORE
Summary: NAS for B cell differentiation from PMID:8228801. IL-10 promotes B cell differentiation.
Reason: IL-10 promotes B cell differentiation, particularly plasma cell differentiation. This is a well-established but non-core function of IL-10 (PMID:8228801, PMID:9184696).
Supporting Evidence:
PMID:8228801
Interleukin 10 (IL-10) has recently been shown to induce normal human B lymphocytes to proliferate and differentiate into immunoglobulin (Ig)-secreting cells.
GO:0042100 B cell proliferation
NAS
PMID:8228801
Interleukin 10 (IL-10) upregulates functional high affinity ... 		KEEP AS NON CORE
Summary: NAS for B cell proliferation from PMID:8228801. IL-10 promotes B cell proliferation in certain contexts.
Reason: IL-10 was originally identified as a B cell growth factor as well as a cytokine synthesis inhibitor. It promotes B cell proliferation of pre-activated B cells (PMID:8228801, PMID:9184696). Keep as non-core.
Supporting Evidence:
PMID:8228801
IL-2 and IL-10 were found to synergize to induce the proliferation and differentiation of B-CLL cells.
GO:0045191 regulation of isotype switching
NAS
PMID:8228801
Interleukin 10 (IL-10) upregulates functional high affinity ... 		KEEP AS NON CORE
Summary: NAS for regulation of isotype switching from PMID:8228801. IL-10 regulates immunoglobulin isotype switching in B cells.
Reason: IL-10 is known to regulate immunoglobulin isotype switching, promoting certain isotype classes. This is a real but non-core function related to IL-10's effects on B cells (PMID:8228801).
Supporting Evidence:
PMID:8228801
normal B cells which proliferated strongly and secreted large amounts of IgM, IgG, and IgA.
GO:0005141 interleukin-10 receptor binding
NAS
PMID:1847510
Isolation and expression of human cytokine synthesis inhibit... 		ACCEPT
Summary: NAS for IL-10 receptor binding from PMID:1847510. This is the seminal paper on IL-10 cDNA cloning (Vieira et al., 1991).
Reason: IL-10 receptor binding is a core molecular function. PMID:1847510 is the original cloning paper for human IL-10 (Vieira et al., PNAS 1991) and established IL-10 as a ligand for its receptor.
Supporting Evidence:
PMID:1847510
cDNA clones encoding human IL-10 (hIL-10) were isolated from a tetanus toxin-specific human T-cell clone.
GO:0008083 growth factor activity
NAS
PMID:1371884
Interleukin 10 is a potent growth and differentiation factor... 		MODIFY
Summary: NAS for growth factor activity from PMID:1371884. IL-10 was early on characterized as having growth factor-like activity on B cells.
Reason: While IL-10 does have proliferation-promoting effects on certain cell types (B cells, mast cells), it is more accurately classified as a cytokine than a growth factor. The term "cytokine activity" (GO:0005125) is more appropriate. Growth factor activity implies a more general proliferative function that does not capture IL-10's primary immunomodulatory role.
Proposed replacements: cytokine activity
Supporting Evidence:
PMID:1371884
human and viral IL-10 stimulate DNA replication of B lymphocytes activated either via their antigen receptor or via their CD40 antigen.
GO:0030097 hemopoiesis
TAS
PMID:11244051
Interleukin-10 and the interleukin-10 receptor. 		KEEP AS NON CORE
Summary: TAS for hemopoiesis from PMID:11244051. IL-10 has effects on hematopoietic cell development.
Reason: IL-10 has effects on hematopoietic cell development and differentiation, particularly on monocyte/macrophage and B cell lineages. This is a broad term but represents a real function. Keep as non-core.
Supporting Evidence:
PMID:11244051
multifunctional cytokine with diverse effects on most hemopoietic cell types.
GO:0032687 negative regulation of interferon-alpha production
NAS
PMID:9637497
Exogenous and endogenous IL-10 regulate IFN-alpha production... 		ACCEPT
Summary: NAS for negative regulation of IFN-alpha production from PMID:9637497. This paper demonstrated that IL-10 reduces IFN-alpha-producing cells and bulk IFN-alpha in response to viral stimulation.
Reason: PMID:9637497 directly demonstrated that IL-10 suppresses IFN-alpha production by PBMCs in response to multiple viruses (HSV-1, Sendai virus, NDV, VSV). This is a specific and well-documented anti-inflammatory function of IL-10.
Supporting Evidence:
PMID:9637497
Human IL-10 (hIL-10) caused reductions in both the frequency of IFN-alpha-producing cells (IPC) and bulk IFN in response to herpes simplex virus type-1 (HSV-1), Sendai virus, Newcastle disease virus, and vesicular stomatitis virus.
GO:0042092 type 2 immune response
TAS
PMID:11244051
Interleukin-10 and the interleukin-10 receptor. 		KEEP AS NON CORE
Summary: TAS for type 2 immune response from PMID:11244051. IL-10 is associated with Th2/type 2 immune responses.
Reason: IL-10 was originally identified as a Th2-derived cytokine and is associated with type 2 immune responses. However, IL-10 is now known to be produced by diverse immune cell types, not exclusively Th2 cells. The association with type 2 immunity is a non-core aspect of IL-10 biology.
Supporting Evidence:
PMID:11244051
IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo.
GO:0042130 negative regulation of T cell proliferation
NAS
PMID:8499633
Human interleukin-10 can directly inhibit T-cell growth 		ACCEPT
Summary: NAS for negative regulation of T cell proliferation from PMID:8499633, which directly demonstrated that IL-10 inhibits T cell growth.
Reason: PMID:8499633 showed that IL-10 directly inhibits T cell growth (55.4% inhibition) when stimulated with immobilized anti-CD3, even in the absence of monocytes. This establishes a direct effect on T cells.
Supporting Evidence:
PMID:8499633
highly purified peripheral blood T cells containing less than 0.1% CD14+ cells and unresponsive to phytohemagglutinin (PHA), were growth-inhibited by IL-10 when stimulated with immobilized OKT3 monoclonal antibody (MoAb; 55.4% inhibition).
GO:0043066 negative regulation of apoptotic process
NAS
PMID:8312229
IL-10 inhibits apoptotic cell death in human T cells starved... 		KEEP AS NON CORE
Summary: NAS for negative regulation of apoptotic process from PMID:8312229, which showed IL-10 inhibits apoptotic cell death in T cells starved of IL-2.
Reason: PMID:8312229 demonstrated that IL-10 inhibits apoptosis in IL-2-deprived T cells. This is a real but context-dependent anti-apoptotic effect of IL-10. Keep as non-core.
Supporting Evidence:
PMID:8312229
IL-10 inhibits apoptotic cell death in human T cells starved of IL-2.
GO:0045347 negative regulation of MHC class II biosynthetic process
TAS
PMID:11244051
Interleukin-10 and the interleukin-10 receptor. 		ACCEPT
Summary: TAS for negative regulation of MHC class II biosynthesis from PMID:11244051.
Reason: IL-10 downregulation of MHC class II expression is a core function, also supported by IDA from PMID:1940799 (PMID:11244051, PMID:1940799).
Supporting Evidence:
PMID:11244051
IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells.
GO:0005576 extracellular region
IPI
PMID:33737461
Structure-based decoupling of the pro- and anti-inflammatory... 		ACCEPT
Summary: IPI for extracellular region from PMID:33737461 (ComplexPortal).
Reason: IL-10 is a secreted protein found in the extracellular region. Correct.
Supporting Evidence:
PMID:33737461
We used a structure-based approach to deconvolute IL-10 pleiotropy by determining the structure of the IL-10 receptor (IL-10R) complex by cryo-electron microscopy at a resolution of 3.5 angstroms.
GO:0045063 T-helper 1 cell differentiation
IDA
PMID:33737461
Structure-based decoupling of the pro- and anti-inflammatory... 		KEEP AS NON CORE
Summary: IDA for T-helper 1 cell differentiation from PMID:33737461 (ComplexPortal). IL-10 can influence Th1/Th2 balance.
Reason: IL-10 can influence T helper cell differentiation, particularly by suppressing Th1 differentiation through inhibition of IL-12 and IFN-gamma production. The annotation says Th1 differentiation, not inhibition of it, so the qualifier from the GOA should be checked. Keep as non-core.
Supporting Evidence:
PMID:33737461
Some variants displayed myeloid-biased activity by suppressing macrophage activation without stimulating inflammatory CD8+ T cells, thereby uncoupling the major opposing functions of IL-10.
GO:0002639 positive regulation of immunoglobulin production
IGI
PMID:22962438
Complement receptor type 1 (CR1, CD35) is a potent inhibitor... 		KEEP AS NON CORE
Summary: IGI for positive regulation of immunoglobulin production from PMID:22962438, with genetic interaction with IL-6 (P60568).
Reason: IL-10 promotes immunoglobulin production by B cells, often in synergy with other cytokines like IL-6. This is consistent with IL-10's B cell-stimulatory functions. Keep as non-core.
Supporting Evidence:
PMID:22962438
CR1 inhibits the differentiation of B cells to plasmablasts and their immunoglobulin production.
GO:1900100 positive regulation of plasma cell differentiation
IGI
PMID:22962438
Complement receptor type 1 (CR1, CD35) is a potent inhibitor... 		KEEP AS NON CORE
Summary: IGI for positive regulation of plasma cell differentiation from PMID:22962438, with genetic interaction with IL-6 (P60568).
Reason: IL-10 promotes plasma cell differentiation, consistent with its B cell stimulatory functions. Keep as non-core.
Supporting Evidence:
PMID:22962438
CR1 inhibits the differentiation of B cells to plasmablasts and their immunoglobulin production.

Core Functions

IL-10 binds its receptor complex comprising IL-10RA (ligand-binding) and IL-10RB (signal-transducing). This is the primary molecular function through which IL-10 initiates all downstream signaling. Supported by NAS (PMID:1847510), IEA, and structural studies (PMID:16982608).

Molecular Function:
interleukin-10 receptor binding
Directly Involved In:
interleukin-10-mediated signaling pathway positive regulation of receptor signaling pathway via JAK-STAT
Cellular Locations:
extracellular region
Supporting Evidence:
  • PMID:1847510
    Seminal paper cloning human IL-10 cDNA and establishing receptor binding.
  • PMID:16982608
    Structural and signaling study of IL-10 receptor interaction.

IL-10 is the prototypical anti-inflammatory cytokine. Cytokine activity is supported by IBA, IDA (PMID:24994464), NAS (PMID:10443688), and IEA evidence.

Molecular Function:
cytokine activity
Directly Involved In:
negative regulation of inflammatory response immune response
Cellular Locations:
extracellular region
Supporting Evidence:
  • PMID:1940799
    IL-10, added to monocytes, strongly inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF at the transcriptional level.
  • PMID:10443688
    Key primary study supporting IL-10 cytokine activity and anti-inflammatory function.

References

GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  • Some ISS annotations transfer from mouse Il10 (P18893) which is appropriate, while others transfer from FasL/TNFSF6 (P06804) which is an inappropriate source for IL-10 annotations due to completely different function.
GO_REF:0000033
Annotation inferences using phylogenetic trees
  • IBA annotations for IL-10 are well-supported and represent core functions.
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  • Many IEA transfers from rat Il10 (P29456) represent peripheral observations (response to xenobiotic, activity, inactivity, carbon monoxide, insulin, estradiol) that are over-annotations for human IL-10 core function.
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
  • IEA annotations for core functions (cytokine activity, extracellular space, immune response, TNF regulation) are correct.
PMID:1940799
Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes.
  • Seminal paper establishing IL-10 as a cytokine synthesis inhibitor.
    "IL-10, added to monocytes, activated by interferon gamma (IFN-gamma), LPS, or combinations of LPS and IFN-gamma at the onset of the cultures, strongly inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF at the transcriptional level."
  • Demonstrated inhibition of cytokine production and MHC class II expression.
    "IL-10, added to monocytes, activated by interferon gamma (IFN-gamma), LPS, or combinations of LPS and IFN-gamma at the onset of the cultures, strongly inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF at the transcriptional level."
PMID:7749983
Cross-linking of OX40 ligand, a member of the TNF/NGF cytokine family, induces proliferation and differentiation in murine splenic B cells
  • This paper is about OX40L (TNFSF4), NOT about IL-10. Two IDA annotations cite this paper for IL-10, which appears to be a reference error.
    "OX40 is a member of the TNF/NGF-receptor family expressed on activated T cells, whose ligand is found on activated T and B cells."
PMID:8312229
IL-10 inhibits apoptotic cell death in human T cells starved of IL-2
  • IL-10 inhibits apoptosis in IL-2-deprived T cells.
    "IL-10 inhibits apoptotic cell death in human T cells starved of IL-2."
PMID:8499633
Human interleukin-10 can directly inhibit T-cell growth
  • IL-10 directly inhibits T cell growth (55.4% inhibition with anti-CD3).
    "Highly purified peripheral blood T cells containing less than 0.1% CD14+ cells and unresponsive to phytohemagglutinin (PHA), were growth-inhibited by IL-10 when stimulated with immobilized OKT3 monoclonal antibody (MoAb; 55.4% inhibition)."
  • Effect is independent of monocytes.
    "Thus, IL-10 can directly inhibit growth and IL-2 production in T cells triggered by immobilized OKT3 MoAb in the absence of monocytes."
PMID:9184696
The apoptosis and proliferation of SAC-activated B cells by IL-10 are associated with changes in Bcl-2, Bcl-xL, and Mcl-1 expression
  • IL-10 has dual effects on B cells depending on activation state -- apoptosis at initiation versus proliferation after pre-activation.
    "the addition of IL-10 at the initiation of activation down-regulated Bcl-xL, Bcl-2, and Mcl-1 expression. At the same time, B cell proliferation was inhibited and apoptotic cell number increased, suggesting the growth arrest and/or apoptosis of B cells."
  • In contrast, IL-10 supported proliferation and differentiation of pre-activated B cells.
    "In contrast, IL-10 failed to down-regulate the Bcl-xL and Bcl-2 expression but rather augmented the expression of Mcl-1 of B cells after preactivation for 48 hr with SAC and IL-2"
PMID:9637497
Exogenous and endogenous IL-10 regulate IFN-alpha production by peripheral blood mononuclear cells in response to viral stimulation
  • IL-10 reduces frequency of IFN-alpha-producing cells and bulk IFN-alpha.
    "Human IL-10 (hIL-10) caused reductions in both the frequency of IFN-alpha-producing cells (IPC) and bulk IFN in response to herpes simplex virus type-1 (HSV-1), Sendai virus, Newcastle disease virus, and vesicular stomatitis virus."
  • Effect seen with HSV-1, Sendai virus, NDV, and VSV stimulation.
    "Human IL-10 (hIL-10) caused reductions in both the frequency of IFN-alpha-producing cells (IPC) and bulk IFN in response to herpes simplex virus type-1 (HSV-1), Sendai virus, Newcastle disease virus, and vesicular stomatitis virus."
PMID:10443688
Tumor necrosis factor alpha decreases, and interleukin-10 increases, the sensitivity of human monocytes to dexamethasone; potential regulation of the glucocorticoid receptor.
  • IL-10 increases the sensitivity of human monocytes to dexamethasone and enhances glucocorticoid receptor concentration, supporting IL-10 anti-inflammatory synergy with glucocorticoids.
    "Pretreatment with TNFalpha diminished, and with IL-10 improved, the ability of dexamethasone to suppress IL-6 secretion in whole-blood cell cultures (P < 0.01 for both) and to enhance IL-1 receptor antagonist secretion by U937 cells (P < 0.05 for both)."
  • IL-10 increased the concentration of dexamethasone binding sites (glucocorticoid receptor) in monocytes.
    "TNFalpha decreased (P < 0.001), while IL-10 increased (P < 0.001), the concentration of dexamethasone binding sites in these cells, with no discernible effect on their binding affinity."
PMID:14971032
Interleukin 10 regulates cell surface and soluble LIR-2 (CD85d) expression on dendritic cells resulting in T cell hyporesponsiveness in vitro
  • IL-10 upregulates LIR-2 on DCs.
    "the inhibitory receptor LIR-2 (leukocyte immunoglobulin-like receptor-2, CD85d) is specifically up-regulated by IL-10 on maturing human DC"
  • Results in T cell hyporesponsiveness.
    "IL-10 renders DC hypostimulatory by up-regulating cell surface LIR-2 and by inhibiting soluble LIR-2 in vitro"
PMID:16982608
Conformational changes mediate interleukin-10 receptor 2 (IL-10R2) binding to IL-10 and assembly of the signaling complex.
  • Key reference for IL-10 receptor interaction and JAK-STAT signaling.
    "Interleukin-10 receptor 2 (IL-10R2) is a critical component of the IL-10.IL-10R1.IL-10R2 complex which regulates IL-10-mediated immunomodulatory responses"
  • Used for protein dimerization, receptor binding, and signaling annotations.
    "The ternary IL-10 signaling complex is assembled in a sequential order with the IL-10.IL-10R1 interaction occurring first followed by engagement of the IL-10R2 chain."
PMID:19262501
A novel regulatory B-cell population in sheep Peyer's patches spontaneously secretes IL-10 and downregulates TLR9-induced IFNalpha responses
  • B cells secrete IL-10 that suppresses multiple pro-inflammatory cytokines.
    "PP cells spontaneously secreted high levels of IL-10, and the primary source of the IL-10 was resting CD5(-)CD11c(-)CD21(+) B cells."
  • Supports TAS annotations for specific cytokine suppression.
    "Neutralization of the IL-10 or depletion of CD21(+) B cells resulted in a significant increase in CpG-induced IFNalpha-response in PPs, suggesting that IL-10 from B cells regulate innate responses in PPs."
PMID:26962683
IL10 inhibits starvation-induced autophagy in hypertrophic scar fibroblasts via cross talk between the IL10-IL10R-STAT3 and IL10-AKT-mTOR pathways
  • IL-10 inhibits autophagy via STAT3/AKT-mTOR crosstalk.
    "IL10 inhibited starvation-induced autophagy and induced the expression of p-AKT and p-STAT3 in HSFs in a dose-dependent manner."
  • Context-specific effect in hypertrophic scar fibroblasts.
    "IL10 inhibits starvation-induced autophagy in hypertrophic scar fibroblasts via cross talk between the IL10-IL10R-STAT3 and IL10-AKT-mTOR pathways."
PMID:32296183
A reference map of the human binary protein interactome
  • HuRI high-throughput Y2H screen.
    "With approximately 53,000 protein-protein interactions, HuRI has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies."
  • Interactions with keratins and other non-immune proteins are likely false positives for a secreted cytokine.
    "we expect HuRI to be depleted for PPIs that depend on post-translational processing of human proteins that the yeast cell is unable to catalyze or that require additional partners to stabilize the interaction."
PMID:11244051
Interleukin-10 and the interleukin-10 receptor.
  • Referenced for hemopoiesis, type 2 immune response, and MHC class II regulation annotations.
    "Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types."
PMID:1847510
Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI.
  • Seminal paper cloning human IL-10 cDNA.
    "cDNA clones encoding human IL-10 (hIL-10) were isolated from a tetanus toxin-specific human T-cell clone."
PMID:8228801
Interleukin 10 (IL-10) upregulates functional high affinity IL-2 receptors on normal and leukemic B lymphocytes.
  • B cell differentiation, proliferation, and isotype switching regulation by IL-10.
    "Interleukin 10 (IL-10) has recently been shown to induce normal human B lymphocytes to proliferate and differentiate into immunoglobulin (Ig)-secreting cells."
PMID:9405662
Identification of functional domains on human interleukin 10
  • Mapped functional domains on IL-10 including chemotaxis-related regions.
    "human IL-10 inhibits chemokine production and is a specific chemotactic factor for CD8+ T cells"
Reactome:R-HSA-449803
IL10 dimer binds IL10RA:JAK1
Reactome:R-HSA-449811
IL10 dimer:2xIL10RA1:JAK1 binds IL10RB:TYK2
Reactome:R-HSA-449855
IL10 dimerizes
Reactome:R-HSA-6784006
STAT3 is phosphorylated by p-Y-JAK1,P-Y-TYK2
Reactome:R-HSA-6784319
JAK1,TYK2 phosphorylate JAK1,TYK2
Reactome:R-HSA-6784323
IL10 dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2 binds STAT3
Reactome:R-HSA-6784324
p-Y-JAK1,p-Y-TYK2 phosphorylate IL10RA
Reactome:R-HSA-6784791
p-Y705-STAT3 dissociates from IL10 dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2:p-Y705-STAT3
Reactome:R-HSA-6789615
Expression of STAT3-upregulated extracellular proteins
Reactome:R-HSA-8981073
Expression of Interleukin-10
Reactome:R-HSA-9664346
IL10 gene produces IL10 protein
PMID:11485736
Crystal structure of the IL-10/IL-10R1 complex reveals a shared receptor binding site.
  • Structural basis of IL-10 binding to IL-10R1 (IL-10RA).
    "Interleukin 10 (IL-10) is a dimeric cytokine that plays a central role in suppressing inflammatory responses. These activities are dependent on the interaction of IL-10 with its high-affinity receptor (IL-10R1)."
PMID:12513909
Comparison of interleukin-22 and interleukin-10 soluble receptor complexes.
  • Compares IL-22 and IL-10 receptor complex formation.
    "IL-22 and IL-10 require different ligand-specific receptor chains (IL-22R and IL-10R1) but share a second receptor chain (IL-10R2) to initiate cellular responses."
PMID:15837194
Same structure, different function crystal structure of the Epstein-Barr virus IL-10 bound to the soluble IL-10R1 chain.
  • Crystal structure of EBV IL-10 bound to IL-10R1, informing human IL-10/receptor interaction.
    "These functional differences have been correlated with the approximately 1000-fold lower affinity of vIL-10, compared to hIL-10, for the IL-10R1 receptor chain."
PMID:20462497
Structure and mechanism of receptor sharing by the IL-10R2 common chain.
  • Structural basis for IL-10R2 (IL-10RB) sharing among IL-10 family cytokines.
    "IL-10R2 is a shared cell surface receptor required for the activation of five class 2 cytokines (IL-10, IL-22, IL-26, IL-28, and IL-29) that play critical roles in host defense."
PMID:35443184
Human IL-10-producing B cells have diverse states that are induced from multiple B cell subsets.
  • Characterizes diverse IL-10-producing B cell populations.
    "Regulatory B cells (Bregs) suppress immune responses through the secretion of interleukin-10 (IL-10)."
PMID:24994464
Low IL10 serum levels as key factor for predicting the sustained virological response to IFNα/ribavirin in Brazilian patients with HCV carrying IL28B CT/TT genotype.
  • Measures IL-10 serum levels in HCV patients, confirming IL-10 as a circulating cytokine.
    "the levels of IL10 seem to influence response to IFNα/RIB therapy"
PMID:23071313
IL-10-induced microRNA-187 negatively regulates TNF-α, IL-6, and IL-12p40 production in TLR4-stimulated monocytes.
  • IL-10 induces miR-187 which suppresses pro-inflammatory cytokine production.
    "we identify miR-187 as an IL-10-dependent miRNA playing a role in IL-10-mediated suppression of TNF-α, IL-6, and the p40 subunit of IL-12"
PMID:16606666
B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma.
  • IL-6 and IL-10 in the tumor microenvironment stimulate macrophage B7-H4 expression, contributing to immunosuppression.
    "Interleukin (IL)-6 and IL-10 are found in high concentrations in the tumor microenvironment. These cytokines stimulate macrophage B7-H4 expression."
PMID:17875732
Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma.
  • Treg cells enable macrophages to produce IL-10 and IL-6, which in turn stimulate B7-H4 expression on macrophages in an autocrine manner.
    "Tumor Treg cells enabled macrophages to spontaneously produce interleukin (IL)-10 and IL-6. Tumor macrophages stimulated B7-H4 expression in an autocrine manner through IL-10 and IL-6."
PMID:33737461
Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10.
  • Decouples IL-10 pro- and anti-inflammatory functions through structural analysis.
    "IL-10 variants with a range of IL-10Rβ binding strengths uncovered substantial differences in response thresholds across immune cell populations, providing a means of manipulating IL-10 cell type selectivity."
PMID:31611251
Biology and therapeutic potential of interleukin-10.
  • Comprehensive review of IL-10 biology and therapeutic applications.
    "The cytokine IL-10 is a key anti-inflammatory mediator ensuring protection of a host from over-exuberant responses to pathogens and microbiota, while playing important roles in other settings as sterile wound healing, autoimmunity, cancer, and homeostasis."
PMID:21857966
WNT5A signaling contributes to Aβ-induced neuroinflammation and neurotoxicity.
  • IL-10 referenced as anti-inflammatory cytokine in neuroinflammation context.
    "activation of Wnt5a signaling elicited the expression of proinflammatory cytokines IL-1β and TNF-α whereas inhibition of Wnt5a signaling attenuated the Aβ-induced expression of the cytokines in cortical cultures."
PMID:21323571
Pro/anti-inflammatory cytokines in the pathogenesis of premature coronary artery disease.
  • IL-10 measured as anti-inflammatory cytokine in coronary artery disease.
    "Proinflammatory interleukin-18 (IL-18), high-sensitivity C-reactive protein (hS-CRP), tumor necrosis factor-alpha (TNF-alpha), and anti-inflammatory IL-10 are involved in the pathogenesis of atherosclerosis."
PMID:16034134
IL-4 and IL-13 induce protection of porcine endothelial cells from killing by human complement and from apoptosis through activation of a phosphatidylinositide 3-kinase/Akt pathway.
  • IL-10 tested as negative control; does not protect endothelial cells from complement or apoptosis.
    "porcine EC incubated with IL-4 or IL-13, but not with IL-10 or IL-11, became protected from killing by complement and apoptosis induced by TNF-alpha plus cycloheximide."
PMID:9847016
Human interleukin 10 suppresses production of inflammatory mediators by LPS-stimulated equine peritoneal macrophages.
  • IL-10 suppresses inflammatory mediator production in LPS-stimulated macrophages.
    "Preincubation of LPS-stimulated peritoneal macrophages with rhuIL-10 caused significant (P<0.05) reduction in secretion of TNF, IL-6, and PGE2, in a dose-dependent manner."
PMID:18383040
Interleukin-10 regulates TNF-alpha-converting enzyme (TACE/ADAM-17) involving a TIMP-3 dependent and independent mechanism.
  • IL-10 regulates TACE/ADAM-17 ectodomain proteolysis activity.
    "In the presence of IL-10, TNF-alpha production and activation of surface TACE was significantly inhibited."
PMID:17449476
Eis (enhanced intracellular survival) protein of Mycobacterium tuberculosis disturbs the cross regulation of T-cells.
  • IL-10 involved in T cell cross-regulation during M. tuberculosis infection.
    "Treatment of T-cells with Eis inhibits ERK1/2, JAK pathway, and subsequent production of tumor necrosis factor-alpha and interleukin-4. On the contrary, there is increased production of interferon-gamma and interleukin-10"
PMID:1371884
Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes.
  • IL-10 identified as a potent growth and differentiation factor for activated B cells.
    "human and viral IL-10 stimulate DNA replication of B lymphocytes activated either via their antigen receptor or via their CD40 antigen."
PMID:22962438
Complement receptor type 1 (CR1, CD35) is a potent inhibitor of B-cell functions in rheumatoid arthritis patients.
  • IL-10 and IL-6 genetic interaction in B cell function and immunoglobulin/plasma cell differentiation.
    "Besides blocking B-cell receptor-induced proliferation, CR1 inhibits the differentiation of B cells to plasmablasts and their immunoglobulin production."
file:human/IL10/IL10-deep-research-falcon.md
Deep research synthesis of IL-10 literature

Deep Research

Falcon

(IL10-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 7 citations 2026-02-14T14:38:25.880413

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive research report: Human IL10 (UniProt P22301)

Identity verification and core definition
- Target match: The gene symbol IL10 encodes human interleukin-10, a soluble, secreted immunomodulatory cytokine also known as cytokine synthesis inhibitory factor, produced by multiple leukocyte subsets; this aligns with the UniProt P22301 description and the IL-10 family identity (class-II, four-helix bundle cytokine family) (https://doi.org/10.3389/fimmu.2023.1161067, Jun 2023; https://doi.org/10.1016/j.trecan.2023.05.003, Sep 2023) (carlini2023themultifacetednature pages 2-3, salkeni2023interleukin10incancer pages 1-2).
- Molecular form: Biologically active IL-10 is a ~36 kDa homodimer stabilized by intrachain disulfide bonds; it signals via a heterotetrameric receptor, confirming the family/domain expectations for IL-10-like cytokines (https://doi.org/10.3389/fimmu.2023.1161067, Jun 2023) (carlini2023themultifacetednature pages 2-3).

Structure, receptor, and signaling
- Receptor architecture: IL-10 binds a heterotetrameric IL-10 receptor composed of two IL-10RA (IL-10R1; ligand-binding) and two IL-10RB (IL-10R2; shared signal-transducing) chains, predominantly on hematopoietic cells (https://doi.org/10.3389/fimmu.2023.1161067, Jun 2023; https://doi.org/10.1016/j.trecan.2023.05.003, Sep 2023) (carlini2023themultifacetednature pages 2-3, salkeni2023interleukin10incancer pages 1-2).
- Proximal signaling: Receptor subunits associate with JAK1 (IL-10RA) and TYK2 (IL-10RB). Ligand engagement activates JAK1/TYK2, leading to STAT3 phosphorylation, STAT3 dimerization, nuclear translocation, and transcription of anti-inflammatory genes (e.g., SOCS3, IL1RN) (https://doi.org/10.1016/j.trecan.2023.05.003, Sep 2023; https://doi.org/10.3389/fimmu.2023.1161067, Jun 2023) (salkeni2023interleukin10incancer pages 1-2, carlini2023themultifacetednature pages 2-3).
- Additional context: The canonical IL-10/STAT3 anti-inflammatory response is a central homeostatic module in macrophages and other myeloid cells; genomic studies map STAT3 target genes downstream of IL-10 and highlight pathway-level regulation (https://doi.org/10.1093/bfgp/elt028, Aug 2013) (hutchins2013theil10stat3mediatedantiinflammatory pages 1-1).

Expression, cellular sources, and localization
- Cellular sources: Initially described as Th2-derived, IL-10 is now known to be produced by diverse myeloid and lymphoid populations, including monocytes/macrophages, dendritic cells, CD4+ T-cell subsets, FOXP3+ Tregs, CD8+ T cells, NK cells, B cells, and neutrophils; certain tumors may also produce IL-10 (https://doi.org/10.1016/j.trecan.2023.05.003, Sep 2023; https://doi.org/10.3389/fimmu.2023.1161067, Jun 2023) (salkeni2023interleukin10incancer pages 1-2, carlini2023themultifacetednature pages 2-3).
- Localization: IL-10 is synthesized as a secreted cytokine and executes its function extracellularly by engaging cell-surface IL-10R on responsive target cells (https://doi.org/10.3389/fimmu.2023.1161067, Jun 2023) (carlini2023themultifacetednature pages 2-3).

Primary functions and pathway role
- Principal role: IL-10 is a master anti-inflammatory cytokine that limits duration/intensity of innate and adaptive responses. In myeloid cells it suppresses inflammatory gene programs downstream of TLRs and cytokines, largely via STAT3-dependent induction of negative regulators (e.g., SOCS3) and transcriptional reprogramming (https://doi.org/10.1093/bfgp/elt028, Aug 2013; https://doi.org/10.3389/fimmu.2023.1161067, Jun 2023) (hutchins2013theil10stat3mediatedantiinflammatory pages 1-1, carlini2023themultifacetednature pages 2-3).
- Context-dependent immunostimulation: In tumors, IL-10 can directly activate resident or exhausted CD8+ T cells (including STAT1/STAT3 signaling), augment cytotoxicity and IFN-γ production, and synergize with checkpoint blockade—illustrating concentration- and context-dependent pleiotropy within the same receptor pathway (https://doi.org/10.1016/j.trecan.2023.05.003, Sep 2023) (salkeni2023interleukin10incancer pages 1-2).

Recent developments and latest research (emphasis 2023–2024)
- Cancer immunotherapy translation: A 2023 expert review synthesizes bench-to-bedside progress with pegylated IL-10 (pegilodecakin), noting early signals (e.g., in RCC) but mixed outcomes overall, and motivates engineered IL-10 variants and tumor-targeted delivery to enhance antitumor CD8+ responses while limiting systemic immunosuppression (https://doi.org/10.1016/j.trecan.2023.05.003, Sep 2023) (salkeni2023interleukin10incancer pages 1-2).
- Engineered IL-10 concepts: Recent preclinical work describes IL-10 fusions (e.g., Fc/antibody fusions, bispecifics) and variants with altered IL-10Rβ engagement to bias T-cell–stimulatory outputs and improve pharmacokinetics; these are entering early clinical testing, though clinical efficacy and toxicity need validation (source summarizes preclinical/early clinical directions; interpret with caution and cross-checking) (https://doi.org/10.3390/cancers17061012, Mar 2025) (elshemi2025il10directedcancerimmunotherapy pages 7-8, elshemi2025il10directedcancerimmunotherapy pages 12-14).
- Epigenetic and metabolic control of the IL-10 anti-inflammatory response: Systems-level analyses emphasize IL-10/STAT3 as a core anti-inflammatory transcriptional module in macrophages and outline genome-wide STAT3 targeting; newer work (beyond the core sources here) is actively dissecting epigenetic mechanisms and metabolic reprogramming that sharpen IL-10 responsiveness in myeloid cells (foundational summary) (https://doi.org/10.1093/bfgp/elt028, Aug 2013) (hutchins2013theil10stat3mediatedantiinflammatory pages 1-1).
- Infectious disease and COVID-19 context: Elevated circulating IL-10 correlates with severity and mortality in acute and post-acute SARS-CoV-2 infection, underscoring its use as a biomarker of dysregulated immunity (https://doi.org/10.3389/fimmu.2023.1161067, Jun 2023) (carlini2023themultifacetednature pages 2-3).

Current applications and clinical/real-world implementations
- Oncology: Pegilodecakin advanced to multiple trials; reviews describe its capacity to expand intratumoral CD8+ T cells and potential synergy with ICIs, with subsequent mixed clinical outcomes and toxicity concerns; next-generation, targeted IL-10 constructs are in early clinical development to improve the therapeutic index (https://doi.org/10.1016/j.trecan.2023.05.003, Sep 2023; https://doi.org/10.3390/cancers17061012, Mar 2025) (salkeni2023interleukin10incancer pages 1-2, elshemi2025il10directedcancerimmunotherapy pages 12-14).
- Inborn errors of IL-10 signaling and VEO-IBD: Biallelic loss-of-function mutations in IL10 or IL10R cause severe, very early-onset enterocolitis; this human genetic evidence establishes the nonredundant role of IL-10 in intestinal immune homeostasis and informs definitive therapies (e.g., hematopoietic stem cell transplantation in IL-10R deficiency—not detailed quantitatively in the sources below) (https://doi.org/10.3389/fimmu.2023.1161067, Jun 2023; https://doi.org/10.3390/ijms26010121, Dec 2024) (carlini2023themultifacetednature pages 2-3, aebisher2024keyinterleukinsin pages 5-7).

Expert opinions and authoritative analyses
- Trends in Cancer (2023) frames IL-10 as a nuanced immunotherapy target whose dual myeloid-suppressive and CD8+-stimulatory activities can be exploited with engineered pharmacology and optimized delivery; it emphasizes STAT3-centric signaling via JAK1/TYK2 and context dependence (https://doi.org/10.1016/j.trecan.2023.05.003, Sep 2023) (salkeni2023interleukin10incancer pages 1-2, salkeni2023interleukin10incancer pages 9-10).
- Frontiers in Immunology (2023) provides a broad, clinically oriented overview of IL-10’s roles in homeostasis, cancer, and infection, detailing molecular identity, receptor composition, and downstream STAT3 signaling and highlighting IL-10 as a biomarker of hyperinflammation in COVID-19 (https://doi.org/10.3389/fimmu.2023.1161067, Jun 2023) (carlini2023themultifacetednature pages 2-3).
- Briefings in Functional Genomics (2013) provides foundational mechanistic analysis of the IL-10/STAT3 anti-inflammatory response in macrophages, mapping STAT3 genomic targets and co-factors; it remains a core conceptual reference for pathway-level understanding (https://doi.org/10.1093/bfgp/elt028, Aug 2013) (hutchins2013theil10stat3mediatedantiinflammatory pages 1-1).

Relevant statistics and quantitative data (from recent sources)
- Molecular weight and oligomeric state: Active IL-10 is a soluble ~36 kDa homodimer (https://doi.org/10.3389/fimmu.2023.1161067, Jun 2023) (carlini2023themultifacetednature pages 2-3).
- Receptor stoichiometry: Signaling requires a heterotetrameric assembly of 2× IL-10RA and 2× IL-10RB subunits with JAK1/TYK2 coupling, leading to STAT3 activation (https://doi.org/10.3389/fimmu.2023.1161067, Jun 2023; https://doi.org/10.1016/j.trecan.2023.05.003, Sep 2023) (carlini2023themultifacetednature pages 2-3, salkeni2023interleukin10incancer pages 1-2).
- Clinical correlation: Elevated IL-10 associates with worse outcomes in acute/post-acute COVID-19 cohorts (qualitative correlation emphasized in review; specific effect sizes vary by study and are not detailed in the cited summary) (https://doi.org/10.3389/fimmu.2023.1161067, Jun 2023) (carlini2023themultifacetednature pages 2-3).

Notes on evidence limits (to maintain rigor)
- Some 2025 preclinical/clinical engineering reports summarized above are secondary and flagged as lower-quality; they are included to illustrate directions but should be cross-validated with primary data as it becomes available (https://doi.org/10.3390/cancers17061012, Mar 2025) (elshemi2025il10directedcancerimmunotherapy pages 12-14, elshemi2025il10directedcancerimmunotherapy pages 7-8).
- Quantitative outcomes for hematopoietic stem cell transplantation in IL-10R deficiency, detailed epigenetic mechanisms of IL-10-mediated repression, and large randomized clinical trial metrics for pegilodecakin are not contained within the high-priority 2023–2024 sources retrieved here; these topics warrant targeted review of primary literature.

Conclusion
Human IL10 (P22301) encodes the canonical IL-10 cytokine, a secreted homodimer that signals through IL-10RA/IL-10RB to activate JAK1/TYK2 and STAT3, establishing a central anti-inflammatory program while exerting context-dependent immunostimulatory effects on CD8+ T cells. 2023 analyses emphasize IL-10’s duality and the need for engineered delivery and receptor engagement to harness anti-tumor benefits without systemic immunosuppression. Human genetics definitively place IL-10 signaling as essential for intestinal immune tolerance, explaining monogenic VEO-IBD when defective and motivating curative strategies. As translational efforts advance, precise control of IL-10’s pleiotropy via structure-guided engineering and targeted delivery remains the key frontier (https://doi.org/10.3389/fimmu.2023.1161067, Jun 2023; https://doi.org/10.1016/j.trecan.2023.05.003, Sep 2023; https://doi.org/10.1093/bfgp/elt028, Aug 2013) (carlini2023themultifacetednature pages 2-3, salkeni2023interleukin10incancer pages 1-2, hutchins2013theil10stat3mediatedantiinflammatory pages 1-1).

References

  1. (carlini2023themultifacetednature pages 2-3): Valentina Carlini, Douglas M. Noonan, Eslam Abdalalem, Delia Goletti, Clementina Sansone, Luana Calabrone, and Adriana Albini. The multifaceted nature of il-10: regulation, role in immunological homeostasis and its relevance to cancer, covid-19 and post-covid conditions. Frontiers in Immunology, Jun 2023. URL: https://doi.org/10.3389/fimmu.2023.1161067, doi:10.3389/fimmu.2023.1161067. This article has 519 citations and is from a peer-reviewed journal.

  2. (salkeni2023interleukin10incancer pages 1-2): Mohamad Adham Salkeni and Aung Naing. Interleukin-10 in cancer immunotherapy: from bench to bedside. Trends in Cancer, 9:716-725, Sep 2023. URL: https://doi.org/10.1016/j.trecan.2023.05.003, doi:10.1016/j.trecan.2023.05.003. This article has 95 citations and is from a peer-reviewed journal.

  3. (hutchins2013theil10stat3mediatedantiinflammatory pages 1-1): A. Hutchins, Diego Diez, and Diego Miranda-Saavedra. The il-10/stat3-mediated anti-inflammatory response: recent developments and future challenges. Briefings in Functional Genomics, 12:489-498, Aug 2013. URL: https://doi.org/10.1093/bfgp/elt028, doi:10.1093/bfgp/elt028. This article has 531 citations and is from a peer-reviewed journal.

  4. (elshemi2025il10directedcancerimmunotherapy pages 7-8): Adel G. El-Shemi, Afnan Alqurashi, Jihan Abdullah Abdulrahman, Hanin Dhaifallah Alzahrani, Khawlah Saad Almwalad, Hadeel Hisham Felfilan, Wahaj Saud Alomiri, Jana Ahmed Aloufi, Ghadeer Hassn Madkhali, Sarah Adel Maqliyah, Jood Bandar Alshahrani, Huda Taj Kamal, Sawsan Hazim Daghistani, Bassem Refaat, and Faisal Minshawi. Il-10-directed cancer immunotherapy: preclinical advances, clinical insights, and future perspectives. Cancers, 17:1012, Mar 2025. URL: https://doi.org/10.3390/cancers17061012, doi:10.3390/cancers17061012. This article has 10 citations and is from a poor quality or predatory journal.

  5. (elshemi2025il10directedcancerimmunotherapy pages 12-14): Adel G. El-Shemi, Afnan Alqurashi, Jihan Abdullah Abdulrahman, Hanin Dhaifallah Alzahrani, Khawlah Saad Almwalad, Hadeel Hisham Felfilan, Wahaj Saud Alomiri, Jana Ahmed Aloufi, Ghadeer Hassn Madkhali, Sarah Adel Maqliyah, Jood Bandar Alshahrani, Huda Taj Kamal, Sawsan Hazim Daghistani, Bassem Refaat, and Faisal Minshawi. Il-10-directed cancer immunotherapy: preclinical advances, clinical insights, and future perspectives. Cancers, 17:1012, Mar 2025. URL: https://doi.org/10.3390/cancers17061012, doi:10.3390/cancers17061012. This article has 10 citations and is from a poor quality or predatory journal.

  6. (aebisher2024keyinterleukinsin pages 5-7): David Aebisher, Dorota Bartusik-Aebisher, Agnieszka Przygórzewska, Piotr Oleś, Paweł Woźnicki, and Aleksandra Kawczyk-Krupka. Key interleukins in inflammatory bowel disease—a review of recent studies. International Journal of Molecular Sciences, 26:121, Dec 2024. URL: https://doi.org/10.3390/ijms26010121, doi:10.3390/ijms26010121. This article has 30 citations and is from a poor quality or predatory journal.

  7. (salkeni2023interleukin10incancer pages 9-10): Mohamad Adham Salkeni and Aung Naing. Interleukin-10 in cancer immunotherapy: from bench to bedside. Trends in Cancer, 9:716-725, Sep 2023. URL: https://doi.org/10.1016/j.trecan.2023.05.003, doi:10.1016/j.trecan.2023.05.003. This article has 95 citations and is from a peer-reviewed journal.

Citations

  1. carlini2023themultifacetednature pages 2-3
  2. aebisher2024keyinterleukinsin pages 5-7
  3. https://doi.org/10.3389/fimmu.2023.1161067,
  4. https://doi.org/10.1016/j.trecan.2023.05.003,
  5. https://doi.org/10.1093/bfgp/elt028,
  6. https://doi.org/10.3390/cancers17061012,
  7. https://doi.org/10.3390/ijms26010121,

📄 View Raw YAML

 
id: P22301
gene_symbol: IL10
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: IL-10 (Interleukin-10, also known as Cytokine Synthesis Inhibitory 
  Factor/CSIF) is the prototypical anti-inflammatory cytokine and founding 
  member of the IL-10 family. It is a secreted homodimeric four-helix-bundle 
  cytokine (~36 kDa dimer) that signals through a heterotetrameric receptor 
  complex comprising two IL-10RA (ligand-binding) and two IL-10RB 
  (signal-transducing) chains. Receptor engagement activates JAK1 (via IL-10RA) 
  and TYK2 (via IL-10RB), leading to STAT3 phosphorylation, dimerization, 
  nuclear translocation, and transcription of anti-inflammatory target genes 
  (e.g., SOCS3, IL1RN). IL-10 is produced by multiple immune cell types 
  including monocytes/macrophages, dendritic cells, T cell subsets (Th1, Th2, 
  Treg), B cells, and NK cells. Its principal function is to suppress 
  inflammatory responses by inhibiting pro-inflammatory cytokine production 
  (TNF, IL-1, IL-6, IL-8, IL-12) in monocytes/macrophages, downregulating MHC 
  class II expression and co-stimulatory molecules, and limiting T cell 
  activation. IL-10 also has immunostimulatory effects on B cells (promoting 
  proliferation, differentiation, and immunoglobulin production) and CD8+ T 
  cells in certain contexts. Loss-of-function mutations in IL10 or IL10R cause 
  very-early-onset inflammatory bowel disease (VEO-IBD), establishing IL-10 
  signaling as essential for intestinal immune homeostasis.
existing_annotations:
- term:
    id: GO:0006955
    label: immune response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation for immune response. IL-10 is a central 
      immunomodulatory cytokine involved in both innate and adaptive immune 
      responses. The phylogenetic inference is well-supported by extensive 
      literature on IL-10 across vertebrates.
    action: ACCEPT
    reason: IL-10 is definitively involved in immune response; this is one of 
      its most fundamental roles. The IBA annotation is well-supported by 
      conserved function across vertebrate IL-10 orthologs and extensive 
      experimental evidence in human, mouse, rat, and zebrafish (PMID:1940799, 
      deep research review).
- term:
    id: GO:0005125
    label: cytokine activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation for cytokine activity. IL-10 is a prototypical 
      cytokine that signals through the IL-10 receptor complex to activate 
      JAK-STAT signaling.
    action: ACCEPT
    reason: Cytokine activity is the core molecular function of IL-10. It is the
      founding member of the IL-10 cytokine family and signals through its 
      receptor complex to mediate its biological effects. This is 
      well-established across all orthologs (PMID:1940799, UniProt P22301).
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation for extracellular space localization. IL-10 is a 
      secreted cytokine that functions in the extracellular space by binding 
      cell-surface receptors.
    action: ACCEPT
    reason: IL-10 contains a signal peptide (residues 1-18) and is secreted. It 
      functions as a soluble homodimer in the extracellular space where it 
      engages the IL-10R complex on target cells (UniProt P22301, deep research 
      review).
- term:
    id: GO:0046427
    label: positive regulation of receptor signaling pathway via JAK-STAT
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation for positive regulation of JAK-STAT signaling. IL-10
      signals through JAK1/TYK2 to activate STAT3 phosphorylation.
    action: ACCEPT
    reason: This is a core aspect of IL-10 signaling. Binding to IL-10RA/IL-10RB
      activates JAK1 and TYK2, leading to STAT3 phosphorylation, which is the 
      canonical downstream signaling pathway (PMID:16982608, deep research 
      review).
- term:
    id: GO:0050728
    label: negative regulation of inflammatory response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation for negative regulation of inflammatory response. 
      IL-10 is the prototypical anti-inflammatory cytokine.
    action: ACCEPT
    reason: This is the single most characteristic function of IL-10. It 
      suppresses pro-inflammatory cytokine production, downregulates MHC class 
      II, and limits inflammatory responses. Conserved across vertebrate 
      orthologs (PMID:1940799, PMID:10443688, deep research review).
- term:
    id: GO:0140105
    label: interleukin-10-mediated signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation for IL-10-mediated signaling pathway. IL-10 is the 
      ligand that initiates this pathway.
    action: ACCEPT
    reason: IL-10 is the defining ligand for the IL-10-mediated signaling 
      pathway. This is essentially tautological for the IL-10 protein itself and
      well-supported by phylogenetic inference (deep research review).
- term:
    id: GO:0005125
    label: cytokine activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation for cytokine activity, consistent with the IBA 
      annotation and multiple IDA annotations for the same term.
    action: ACCEPT
    reason: Redundant with IBA and IDA annotations but correct. IL-10 is 
      unambiguously a cytokine (UniProt P22301, PMID:1940799).
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation for extracellular region. IL-10 is a secreted 
      protein.
    action: ACCEPT
    reason: Broader than extracellular space (GO:0005615) but still correct. 
      IL-10 is secreted and functions in the extracellular region (UniProt 
      P22301).
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation for extracellular space, consistent with IBA 
      annotation.
    action: ACCEPT
    reason: Redundant with IBA annotation but correct. IL-10 is a secreted 
      cytokine found in extracellular space (UniProt P22301).
- term:
    id: GO:0006955
    label: immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation for immune response, consistent with IBA annotation.
    action: ACCEPT
    reason: Redundant with IBA annotation but correct. IL-10 is a key immune 
      response cytokine (PMID:1940799).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11485736
  review:
    summary: IPI protein binding annotation based on interaction with IL-10RA 
      (Q13651). PMID:11485736 likely describes IL-10/IL-10RA interaction 
      studies.
    action: MODIFY
    reason: The interaction between IL-10 and IL-10RA is physiologically 
      critical and well-characterized, but "protein binding" is too vague. This 
      should be annotated as interleukin-10 receptor binding (GO:0005141) which 
      more precisely captures the functional nature of this interaction.
    proposed_replacement_terms:
    - id: GO:0005141
      label: interleukin-10 receptor binding
    supported_by:
    - reference_id: PMID:11485736
      supporting_text: Interleukin 10 (IL-10) is a dimeric cytokine that plays a
        central role in suppressing inflammatory responses. These activities are
        dependent on the interaction of IL-10 with its high-affinity receptor 
        (IL-10R1).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12513909
  review:
    summary: IPI protein binding based on interaction with IL-10RB (Q08334) and 
      IL-10RA (Q13651). PMID:12513909 compares IL-22 and IL-10 soluble receptor 
      complexes.
    action: MODIFY
    reason: IL-10 binds both IL-10RA and IL-10RB as part of its receptor 
      complex. "Protein binding" is uninformative; should be interleukin-10 
      receptor binding (GO:0005141).
    proposed_replacement_terms:
    - id: GO:0005141
      label: interleukin-10 receptor binding
    supported_by:
    - reference_id: PMID:12513909
      supporting_text: IL-22 and IL-10 require different ligand-specific 
        receptor chains (IL-22R and IL-10R1) but share a second receptor chain 
        (IL-10R2) to initiate cellular responses.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15837194
  review:
    summary: IPI protein binding based on interaction with IL-10RA (Q13651).
    action: MODIFY
    reason: Another IL-10/IL-10RA interaction. Should be annotated as 
      interleukin-10 receptor binding (GO:0005141) for specificity.
    proposed_replacement_terms:
    - id: GO:0005141
      label: interleukin-10 receptor binding
    supported_by:
    - reference_id: PMID:15837194
      supporting_text: These functional differences have been correlated with 
        the approximately 1000-fold lower affinity of vIL-10, compared to 
        hIL-10, for the IL-10R1 receptor chain.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20462497
  review:
    summary: IPI protein binding from PMID:20462497, which describes the 
      structure and mechanism of receptor sharing by IL-10R2 (IL-10RB) common 
      chain. Interaction with Q08334 (IL-10RB) and Q13651 (IL-10RA).
    action: MODIFY
    reason: This paper provides structural evidence for IL-10 binding its 
      receptor chains. Should be annotated as interleukin-10 receptor binding 
      (GO:0005141).
    proposed_replacement_terms:
    - id: GO:0005141
      label: interleukin-10 receptor binding
    supported_by:
    - reference_id: PMID:20462497
      supporting_text: IL-10R2 is a shared cell surface receptor required for 
        the activation of five class 2 cytokines (IL-10, IL-22, IL-26, IL-28, 
        and IL-29) that play critical roles in host defense.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: IPI protein binding from the HuRI (Human Reference Interactome) 
      high-throughput yeast two-hybrid study (PMID:32296183). Interacting 
      partners include O76003, P0DPK4, P25490, P60410, Q8IUG1, Q9BYQ7 -- several
      of which are keratin-associated proteins or other unlikely interaction 
      partners for a secreted cytokine.
    action: REMOVE
    reason: PMID:32296183 is a large-scale Y2H screen. The interacting partners 
      detected (keratins, KRTAP proteins) are likely non-physiological false 
      positives for IL-10, which is a secreted extracellular cytokine. These 
      interactions lack biological plausibility and are not supported by any 
      other evidence.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16982608
  review:
    summary: IPI protein binding with IL-10RA (Q13651) from PMID:16982608. This 
      paper likely describes IL-10 structural biology and receptor interaction.
    action: MODIFY
    reason: IL-10/IL-10RA interaction. Should be interleukin-10 receptor binding
      (GO:0005141).
    proposed_replacement_terms:
    - id: GO:0005141
      label: interleukin-10 receptor binding
    supported_by:
    - reference_id: PMID:16982608
      supporting_text: Interleukin-10 receptor 2 (IL-10R2) is a critical 
        component of the IL-10.IL-10R1.IL-10R2 complex which regulates 
        IL-10-mediated immunomodulatory responses.
- term:
    id: GO:0001818
    label: negative regulation of cytokine production
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from rat Il10 (P29456). IL-10 is well-established as a
      negative regulator of cytokine production.
    action: ACCEPT
    reason: This is a core function of IL-10. It was originally named Cytokine 
      Synthesis Inhibitory Factor (CSIF) precisely because it inhibits cytokine 
      production by monocytes (PMID:1940799). The IEA transfer is 
      well-supported.
- term:
    id: GO:0001938
    label: positive regulation of endothelial cell proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from mouse Il10 (P18893) for positive regulation of 
      endothelial cell proliferation. This is a non-immune pleiotropic effect.
    action: MARK_AS_OVER_ANNOTATED
    reason: While IL-10 has been reported to have effects on endothelial cells, 
      this is a downstream pleiotropic effect rather than a core function. IL-10
      is primarily an immune regulatory cytokine. The annotation represents an 
      over-annotation of a secondary effect observed in specific experimental 
      conditions.
- term:
    id: GO:0005141
    label: interleukin-10 receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from rat Il10 (P29456). IL-10 receptor binding is the 
      primary molecular function through which IL-10 initiates signaling.
    action: ACCEPT
    reason: IL-10 receptor binding is a core molecular function. IL-10 binds the
      IL-10RA/IL-10RB receptor complex to initiate downstream JAK-STAT signaling
      (UniProt P22301, deep research review).
- term:
    id: GO:0008285
    label: negative regulation of cell population proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from mouse Il10 (P18893). IL-10 can inhibit 
      proliferation of certain cell types including T cells and some other cell 
      populations.
    action: KEEP_AS_NON_CORE
    reason: IL-10 can inhibit T cell proliferation (PMID:8499633) and has 
      anti-proliferative effects on some cell types, but this is a broad term 
      that does not capture the specific immune regulatory context. Acceptable 
      as a non-core annotation.
    supported_by:
    - reference_id: PMID:8499633
      supporting_text: Human interleukin-10 (IL-10) inhibits T-cell 
        proliferation and cytokine production in the presence of monocytes.
- term:
    id: GO:0009410
    label: response to xenobiotic stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from rat Il10 (P29456). IL-10 expression may be 
      induced by xenobiotic stimuli in rats, but this is not a core function for
      human IL-10.
    action: MARK_AS_OVER_ANNOTATED
    reason: Response to xenobiotic stimulus is a peripheral observation likely 
      from rodent studies where IL-10 expression was measured after xenobiotic 
      exposure. This does not represent a core function of IL-10 as a cytokine 
      and is an over-annotation from ortholog transfer.
- term:
    id: GO:0014823
    label: response to activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from rat Il10 (P29456). IL-10 levels may change with 
      physical activity in rats, but this is not a core function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Response to activity (physical exercise) is a peripheral 
      observation. IL-10 levels may change as part of general immune modulation 
      during exercise, but this does not represent a core function of the 
      cytokine itself.
- term:
    id: GO:0014854
    label: response to inactivity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from rat Il10 (P29456). Similar to response to 
      activity, this is a peripheral observation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Response to inactivity is a peripheral observation from rodent 
      studies. Not a core function of IL-10 as an anti-inflammatory cytokine.
- term:
    id: GO:0032496
    label: response to lipopolysaccharide
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from rat Il10 (P29456). IL-10 is induced by LPS and 
      also modulates the response to LPS.
    action: KEEP_AS_NON_CORE
    reason: IL-10 is both induced by LPS stimulation and acts to suppress 
      LPS-induced inflammatory responses. This is a well-established aspect of 
      IL-10 biology (PMID:14971032, PMID:10443688), though it represents a 
      stimulus-response context rather than core function per se.
- term:
    id: GO:0032720
    label: negative regulation of tumor necrosis factor production
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation for negative regulation of TNF production. IL-10 is 
      a potent suppressor of TNF production by monocytes/macrophages.
    action: ACCEPT
    reason: Suppression of TNF production was one of the earliest identified 
      functions of IL-10 (PMID:1940799) and is a core anti-inflammatory 
      activity. The TAS annotation from PMID:19262501 also supports this. This 
      IEA annotation is correct.
- term:
    id: GO:0032868
    label: response to insulin
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from rat Il10 (P29456). IL-10 levels may be affected 
      by insulin in metabolic contexts.
    action: MARK_AS_OVER_ANNOTATED
    reason: Response to insulin is a peripheral metabolic observation from 
      rodent studies. While there are links between IL-10 and metabolic 
      regulation, this is not a core function of IL-10 as an immune cytokine.
- term:
    id: GO:0034115
    label: negative regulation of heterotypic cell-cell adhesion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from mouse Il10 (P18893). IL-10 can downregulate 
      adhesion molecules such as ICAM-1 on monocytes.
    action: KEEP_AS_NON_CORE
    reason: IL-10 downregulates ICAM-1 and other adhesion molecules on monocytes
      (PMID:7512027 per UniProt), which affects cell-cell adhesion. This is a 
      downstream consequence of IL-10's anti-inflammatory program rather than a 
      core function, but it is a real effect.
- term:
    id: GO:0034465
    label: response to carbon monoxide
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from rat Il10 (P29456). IL-10 expression may be 
      induced by carbon monoxide in rat models.
    action: MARK_AS_OVER_ANNOTATED
    reason: Response to carbon monoxide is a highly peripheral observation from 
      rodent studies. This is not a core function of IL-10 and represents an 
      over-annotation via ortholog transfer.
- term:
    id: GO:0043032
    label: positive regulation of macrophage activation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from rat Il10 (P29456). This seems contradictory since
      IL-10 is primarily known to suppress macrophage activation, not promote 
      it.
    action: UNDECIDED
    reason: IL-10 is primarily known as an inhibitor of macrophage activation 
      (suppressing pro-inflammatory cytokine production and MHC class II 
      expression). While IL-10 can have some activating effects on macrophages 
      (e.g., promoting alternative/M2 activation), the annotation of "positive 
      regulation of macrophage activation" without qualification is potentially 
      misleading. The underlying rodent evidence is not accessible to verify.
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from rat Il10 (P29456). IL-10 can inhibit apoptosis in
      certain cell types.
    action: KEEP_AS_NON_CORE
    reason: IL-10 has been shown to inhibit apoptosis in T cells starved of IL-2
      (PMID:8312229) and can promote survival of certain immune cell types. This
      is a real but non-core effect of IL-10 signaling.
    supported_by:
    - reference_id: PMID:8312229
      supporting_text: IL-10 inhibits apoptotic cell death in human T cells 
        starved of IL-2.
- term:
    id: GO:0043524
    label: negative regulation of neuron apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from rat Il10 (P29456). IL-10 has been reported to 
      have neuroprotective effects in certain rodent models.
    action: MARK_AS_OVER_ANNOTATED
    reason: Neuroprotective effects of IL-10 have been observed in rodent models
      of neuroinflammation, but this is a highly context-dependent downstream 
      effect rather than a core function of this immune cytokine. 
      Over-annotation via ortholog transfer.
- term:
    id: GO:0045019
    label: negative regulation of nitric oxide biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from rat Il10 (P29456). IL-10 suppresses iNOS 
      expression and NO production in activated macrophages.
    action: KEEP_AS_NON_CORE
    reason: IL-10 suppresses iNOS expression and nitric oxide production as part
      of its anti-inflammatory program in macrophages. This is a documented 
      downstream effect of IL-10-mediated suppression of inflammatory gene 
      expression, though not a core molecular function.
- term:
    id: GO:0045787
    label: positive regulation of cell cycle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from mouse Il10 (P18893). IL-10 can promote cell cycle
      progression in certain cell types.
    action: MARK_AS_OVER_ANNOTATED
    reason: While IL-10 can promote proliferation of certain cell types (e.g., B
      cells, mast cells), a generic "positive regulation of cell cycle" 
      annotation is over-broad and does not capture the specific immune context.
      This is an over-annotation.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from mouse Il10 (P18893). IL-10 signaling leads to 
      STAT3-dependent transcriptional activation of anti-inflammatory genes.
    action: KEEP_AS_NON_CORE
    reason: IL-10 does activate transcription of specific genes via STAT3, but 
      this is an extremely broad GO term. It is technically correct as a 
      downstream effect of IL-10 signaling but not informative about IL-10's 
      specific function.
- term:
    id: GO:0050807
    label: regulation of synapse organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from rat Il10 (P29456). IL-10 has been implicated in 
      neuroimmune contexts.
    action: MARK_AS_OVER_ANNOTATED
    reason: Regulation of synapse organization is a very peripheral observation 
      from rodent neuroimmune studies. This is not a core function of IL-10 as 
      an immune cytokine and represents an over-annotation via ortholog 
      transfer.
- term:
    id: GO:0051384
    label: response to glucocorticoid
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from rat Il10 (P29456). Glucocorticoids can regulate 
      IL-10 expression.
    action: KEEP_AS_NON_CORE
    reason: IL-10 expression is known to be regulated by glucocorticoids (also 
      supported by IDA annotation from PMID:10443688). While this describes 
      regulation of IL-10 rather than a function of IL-10, the annotation is not
      wrong per se. Keep as non-core.
- term:
    id: GO:0071392
    label: cellular response to estradiol stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from rat Il10 (P29456). IL-10 levels may respond to 
      estradiol in rodent studies.
    action: MARK_AS_OVER_ANNOTATED
    reason: Response to estradiol is a peripheral hormonal regulation 
      observation from rodent studies. Not a core function of IL-10.
- term:
    id: GO:0097421
    label: liver regeneration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from rat Il10 (P29456). IL-10 may play a role in liver
      regeneration in rodent models.
    action: MARK_AS_OVER_ANNOTATED
    reason: Liver regeneration is a highly tissue-specific and peripheral 
      observation. While IL-10 may be expressed during liver regeneration, this 
      is not a core function of this immune cytokine.
- term:
    id: GO:1903034
    label: regulation of response to wounding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from mouse Il10 (P18893). IL-10 modulates wound 
      healing by regulating inflammatory responses.
    action: KEEP_AS_NON_CORE
    reason: IL-10 does modulate wound healing through its anti-inflammatory 
      properties, which is an extension of its core immune regulatory function. 
      Keep as non-core since it is a contextual application of the core 
      function.
- term:
    id: GO:1903377
    label: negative regulation of oxidative stress-induced neuron intrinsic 
      apoptotic signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from mouse Il10 (P18893). Highly specific 
      neuroprotective annotation from rodent models.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is an extremely specific neuroprotective annotation from mouse 
      studies. IL-10 is not a neuron-specific factor; this represents a highly 
      contextual observation from specific experimental paradigms that does not 
      reflect a core function.
- term:
    id: GO:1903672
    label: positive regulation of sprouting angiogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from mouse Il10 (P18893). IL-10 has been implicated in
      angiogenesis regulation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Regulation of angiogenesis is a downstream pleiotropic effect rather
      than a core function of IL-10 as an immune cytokine. Over-annotation from 
      ortholog transfer.
- term:
    id: GO:1904706
    label: negative regulation of vascular associated smooth muscle cell 
      proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from mouse Il10 (P18893). IL-10 may inhibit vascular 
      smooth muscle cell proliferation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Vascular smooth muscle cell proliferation regulation is a peripheral
      non-immune effect. Over-annotation from ortholog transfer.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:7749983
  review:
    summary: IDA annotation from PMID:7749983. This paper is about OX40L 
      (TNFSF4), not about IL-10, so the reference is misattributed. However, 
      IL-10 signaling through STAT3 does activate transcription of target genes,
      so the annotation itself is not wrong -- it is just a very broad term. 
      Consistent with the IEA annotation for the same term which is marked 
      KEEP_AS_NON_CORE.
    action: KEEP_AS_NON_CORE
    reason: The reference PMID:7749983 is misattributed (it describes OX40L 
      cross-linking on murine B cells, not IL-10). Nevertheless, IL-10 does 
      positively regulate transcription by RNA polymerase II via STAT3 signaling
      (PMID:16982608), so the annotation is biologically correct though overly 
      broad. This is consistent with the IEA annotation for the same GO term. 
      Kept as non-core because the term does not capture IL-10's specific 
      function.
    supported_by:
    - reference_id: PMID:7749983
      supporting_text: OX40 is a member of the TNF/NGF-receptor family expressed
        on activated T cells, whose ligand is found on activated T and B cells
- term:
    id: GO:0140105
    label: interleukin-10-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:7749983
  review:
    summary: IDA annotation from PMID:7749983. The reference is misattributed 
      (paper is about OX40L/TNFSF4, not IL-10). However, IL-10 is the defining 
      ligand for the IL-10-mediated signaling pathway, so the annotation itself 
      is correct and well-supported by IBA, IDA from PMID:10443688, and IDA from
      PMID:24994464.
    action: ACCEPT
    reason: IL-10 is the defining ligand for the IL-10-mediated signaling 
      pathway; this is a core function that is essentially tautological. The 
      reference PMID:7749983 is misattributed (it describes OX40L cross-linking 
      on murine B cells), but the annotation is strongly supported by multiple 
      other evidence lines including IBA (GO_REF:0000033), IDA (PMID:10443688), 
      and IDA (PMID:24994464). Accepting the annotation despite the reference 
      error because the biology is unambiguous.
    supported_by:
    - reference_id: PMID:7749983
      supporting_text: OX40 is a member of the TNF/NGF-receptor family expressed
        on activated T cells, whose ligand is found on activated T and B cells
- term:
    id: GO:0140105
    label: interleukin-10-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:10443688
  review:
    summary: IDA annotation for IL-10-mediated signaling pathway from 
      PMID:10443688. This publication is not available for review but is 
      frequently cited for IL-10 annotations and is likely a primary study of 
      IL-10 signaling.
    action: ACCEPT
    reason: IL-10 is the defining ligand for the IL-10-mediated signaling 
      pathway. This PMID is cited for multiple IL-10 annotations and appears to 
      be a key primary study. The annotation is consistent with the known 
      biology of IL-10.
    supported_by:
    - reference_id: PMID:10443688
      supporting_text: interleukin (IL)-10 (an anti-inflammatory cytokine) to 
        differentially regulate the sensitivity of human monocytes/macrophages 
        to glucocorticoids.
- term:
    id: GO:0046427
    label: positive regulation of receptor signaling pathway via JAK-STAT
  evidence_type: IDA
  original_reference_id: PMID:16982608
  review:
    summary: IDA annotation for positive regulation of JAK-STAT signaling from 
      PMID:16982608. This paper likely describes the structural basis of IL-10 
      signaling through its receptor complex to activate JAK1/TYK2/STAT3.
    action: ACCEPT
    reason: This is a core aspect of IL-10 function. IL-10 engagement of 
      IL-10RA/IL-10RB activates JAK1 and TYK2, leading to STAT3 phosphorylation.
      PMID:16982608 is cited multiple times for IL-10 receptor and signaling 
      annotations, suggesting it is a key structural/functional study (deep 
      research review).
    supported_by:
    - reference_id: PMID:16982608
      supporting_text: The ternary IL-10 signaling complex is assembled in a 
        sequential order with the IL-10.IL-10R1 interaction occurring first 
        followed by engagement of the IL-10R2 chain.
- term:
    id: GO:0050864
    label: regulation of B cell activation
  evidence_type: IDA
  original_reference_id: PMID:35443184
  review:
    summary: IDA annotation for regulation of B cell activation from 
      PMID:35443184. IL-10 has well-established effects on B cells.
    action: KEEP_AS_NON_CORE
    reason: IL-10 regulates B cell activation, which is a real but non-core 
      function relative to its primary anti-inflammatory role. IL-10 was 
      originally characterized as a B cell growth factor as well as a cytokine 
      synthesis inhibitor (PMID:9184696, deep research review). Keep as 
      non-core.
    supported_by:
    - reference_id: PMID:35443184
      supporting_text: Regulatory B cells (Bregs) suppress immune responses 
        through the secretion of interleukin-10 (IL-10). This immunomodulatory 
        capacity holds therapeutic potential, yet a definitional immunophenotype
        for enumeration and prospective isolation of B cells capable of IL-10 
        production remains elusive.
- term:
    id: GO:0005125
    label: cytokine activity
  evidence_type: IDA
  original_reference_id: PMID:24994464
  review:
    summary: IDA annotation for cytokine activity from PMID:24994464 (about IL10
      serum levels in HCV patients). This confirms IL-10 functions as a 
      circulating cytokine.
    action: ACCEPT
    reason: Cytokine activity is the core molecular function of IL-10. Multiple 
      lines of evidence support this (PMID:1940799, PMID:24994464, IBA, IEA).
    supported_by:
    - reference_id: PMID:24994464
      supporting_text: the levels of IL10 seem to influence response to IFNα/RIB
        therapy.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IDA
  original_reference_id: PMID:24994464
  review:
    summary: IDA for extracellular space from PMID:24994464 (IL10 serum levels).
    action: ACCEPT
    reason: IL-10 is a secreted cytokine detected in serum/plasma. Extracellular
      space localization is well-established.
    supported_by:
    - reference_id: PMID:24994464
      supporting_text: IL10 serum levels could be further explored as a useful 
        algorithm for identify the CT/TT SVR patients.
- term:
    id: GO:0140105
    label: interleukin-10-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:24994464
  review:
    summary: IDA for IL-10-mediated signaling pathway from PMID:24994464.
    action: ACCEPT
    reason: IL-10 is the defining ligand for IL-10-mediated signaling. This is a
      core annotation well-supported by multiple evidence lines.
    supported_by:
    - reference_id: PMID:24994464
      supporting_text: the levels of IL10 seem to influence response to IFNα/RIB
        therapy.
- term:
    id: GO:0071222
    label: cellular response to lipopolysaccharide
  evidence_type: IDA
  original_reference_id: PMID:23071313
  review:
    summary: IDA annotation for cellular response to LPS from PMID:23071313. 
      IL-10 is both induced by and modulates the cellular response to LPS.
    action: KEEP_AS_NON_CORE
    reason: IL-10 modulates the cellular response to LPS by suppressing 
      pro-inflammatory cytokine production. This is a well-established aspect of
      IL-10 biology but represents a specific stimulus-response context rather 
      than core function.
    supported_by:
    - reference_id: PMID:23071313
      supporting_text: IL-10 is a potent anti-inflammatory molecule that, in 
        phagocytes, negatively targets cytokine expression at transcriptional 
        and posttranscriptional levels.
- term:
    id: GO:1902895
    label: positive regulation of miRNA transcription
  evidence_type: IDA
  original_reference_id: PMID:23071313
  review:
    summary: IDA annotation for positive regulation of miRNA transcription from 
      PMID:23071313. IL-10 has been shown to regulate miRNA expression as part 
      of its signaling.
    action: KEEP_AS_NON_CORE
    reason: IL-10 signaling through STAT3 can regulate miRNA transcription as a 
      downstream effect. This is a mechanistic detail of IL-10 signaling rather 
      than a core function, but it is experimentally supported. Keep as 
      non-core.
    supported_by:
    - reference_id: PMID:23071313
      supporting_text: we identify miR-187 as an IL-10-dependent miRNA playing a
        role in IL-10-mediated suppression of TNF-α, IL-6, and the p40 subunit 
        of IL-12 (IL-12p40) produced by primary human monocytes following 
        activation of Toll-like receptor 4 (TLR4).
- term:
    id: GO:0050728
    label: negative regulation of inflammatory response
  evidence_type: IDA
  original_reference_id: PMID:10443688
  review:
    summary: IDA annotation for negative regulation of inflammatory response 
      from PMID:10443688. This is a core function of IL-10.
    action: ACCEPT
    reason: This is the single most important function of IL-10. The 
      anti-inflammatory activity of IL-10 has been demonstrated in numerous 
      experimental systems (PMID:1940799, PMID:10443688, deep research review).
    supported_by:
    - reference_id: PMID:10443688
      supporting_text: IL-10 acts synergistically with glucocorticoids. This is 
        accompanied by opposite glucocorticoid receptor changes, respectively 
        opposing and favoring glucocorticoid actions.
- term:
    id: GO:0001818
    label: negative regulation of cytokine production
  evidence_type: IDA
  original_reference_id: PMID:1940799
  review:
    summary: IDA annotation for negative regulation of cytokine production from 
      PMID:1940799. This is the seminal paper by de Waal Malefyt et al. (1991) 
      establishing IL-10 as a cytokine synthesis inhibitor.
    action: ACCEPT
    reason: This is one of the most fundamental annotations for IL-10. 
      PMID:1940799 demonstrated that IL-10 inhibits cytokine synthesis by human 
      monocytes. IL-10 was originally named Cytokine Synthesis Inhibitory Factor
      (CSIF) based on this activity.
    supported_by:
    - reference_id: PMID:1940799
      supporting_text: 'Interleukin 10(IL-10) inhibits cytokine synthesis by human
        monocytes: an autoregulatory role of IL-10 produced by monocytes.'
- term:
    id: GO:0010507
    label: negative regulation of autophagy
  evidence_type: IDA
  original_reference_id: PMID:26962683
  review:
    summary: IDA annotation for negative regulation of autophagy from 
      PMID:26962683, which showed IL-10 inhibits starvation-induced autophagy in
      hypertrophic scar fibroblasts via STAT3/AKT-mTOR signaling crosstalk.
    action: KEEP_AS_NON_CORE
    reason: IL-10 has been shown to inhibit autophagy in hypertrophic scar 
      fibroblasts via crosstalk between IL10-IL10R-STAT3 and IL10-AKT-mTOR 
      pathways (PMID:26962683). This is a real but highly context-specific 
      effect, not a core function of IL-10.
    supported_by:
    - reference_id: PMID:26962683
      supporting_text: IL10 inhibits starvation-induced autophagy in 
        hypertrophic scar fibroblasts via cross talk between the 
        IL10-IL10R-STAT3 and IL10-AKT-mTOR pathways.
- term:
    id: GO:0045347
    label: negative regulation of MHC class II biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:1940799
  review:
    summary: IDA annotation for negative regulation of MHC class II biosynthetic
      process from PMID:1940799. IL-10 downregulates MHC class II expression on 
      monocytes.
    action: ACCEPT
    reason: IL-10 downregulation of MHC class II expression on monocytes and 
      macrophages is a core function directly related to its immune suppressive 
      activity (PMID:1940799, PMID:8144879 per UniProt, deep research review).
    supported_by:
    - reference_id: PMID:1940799
      supporting_text: 'Interleukin 10(IL-10) inhibits cytokine synthesis by human
        monocytes: an autoregulatory role of IL-10 produced by monocytes.'
- term:
    id: GO:0046983
    label: protein dimerization activity
  evidence_type: IDA
  original_reference_id: PMID:16982608
  review:
    summary: IDA annotation for protein dimerization activity from 
      PMID:16982608. IL-10 functions as a homodimer.
    action: ACCEPT
    reason: IL-10 forms a non-covalent homodimer as its biologically active 
      form. The dimer is stabilized by domain swapping and intrachain disulfide 
      bonds. This is well-established from crystal structures and biochemical 
      studies (UniProt P22301, PMID:8364028, deep research review).
    supported_by:
    - reference_id: PMID:16982608
      supporting_text: These studies highlight the importance of structure in 
        regulating low affinity protein-protein interactions and IL-10 signal 
        transduction.
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:16606666
  review:
    summary: IDA annotation for positive regulation of transcription from 
      PMID:16606666. IL-10 signaling through STAT3 activates transcription of 
      target genes.
    action: KEEP_AS_NON_CORE
    reason: IL-10 does activate transcription via STAT3 signaling. This is 
      technically correct but is a very broad term. The specific transcriptional
      effects (anti-inflammatory gene induction) are better captured by other 
      annotations. Keep as non-core.
    supported_by:
    - reference_id: PMID:16606666
      supporting_text: Interleukin (IL)-6 and IL-10 are found in high 
        concentrations in the tumor microenvironment. These cytokines stimulate 
        macrophage B7-H4 expression.
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IMP
  original_reference_id: PMID:17875732
  review:
    summary: IMP annotation for positive regulation of transcription from 
      PMID:17875732. This paper showed that tumor Treg cells enable macrophages 
      to produce IL-10 and IL-6, and that tumor macrophages stimulate B7-H4 
      expression in an autocrine manner through IL-10 and IL-6. IL-10 thus 
      indirectly promotes transcription of B7-H4 in this tumor microenvironment 
      context.
    action: KEEP_AS_NON_CORE
    reason: PMID:17875732 demonstrates that IL-10 (produced by Treg-stimulated 
      macrophages) stimulates B7-H4 expression on macrophages in ovarian 
      carcinoma, which constitutes positive regulation of transcription. This is
      consistent with IL-10's known ability to activate STAT3-dependent gene 
      transcription and with the IDA annotation for the same term (GO:0045893) 
      from PMID:16606666, which is also marked KEEP_AS_NON_CORE. The 
      transcriptional regulation is a downstream consequence of IL-10 signaling 
      rather than a core function.
    supported_by:
    - reference_id: PMID:17875732
      supporting_text: Tumor Treg cells enabled macrophages to spontaneously 
        produce interleukin (IL)-10 and IL-6. Tumor macrophages stimulated B7-H4
        expression in an autocrine manner through IL-10 and IL-6.
- term:
    id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  evidence_type: NAS
  original_reference_id: PMID:33737461
  review:
    summary: NAS annotation for JAK-STAT signaling from PMID:33737461 
      (ComplexPortal). IL-10 signals through its receptor complex to activate 
      JAK-STAT signaling.
    action: ACCEPT
    reason: IL-10 signaling through JAK1/TYK2/STAT3 is a core pathway. This NAS 
      annotation from ComplexPortal is consistent with the well-established 
      signaling mechanism (deep research review).
    supported_by:
    - reference_id: PMID:33737461
      supporting_text: We used a structure-based approach to deconvolute IL-10 
        pleiotropy by determining the structure of the IL-10 receptor (IL-10R) 
        complex by cryo-electron microscopy at a resolution of 3.5 angstroms.
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: NAS
  original_reference_id: PMID:31611251
  review:
    summary: NAS annotation for positive regulation of cell proliferation from 
      PMID:31611251 (ComplexPortal).
    action: KEEP_AS_NON_CORE
    reason: IL-10 can promote proliferation of certain cell types, particularly 
      B cells and mast cells. However, it also inhibits proliferation of other 
      cell types (T cells). This is a context-dependent effect, keep as 
      non-core.
    supported_by:
    - reference_id: PMID:31611251
      supporting_text: IL-10 (Fiorentino et al., 1989; Moore et al., 1990) is 
        the founding member of a family of cytokines that also includes IL-19, 
        IL-20, IL-22, IL-24, IL-26, IL-28A, IL-28B, and IL-29
- term:
    id: GO:0019221
    label: cytokine-mediated signaling pathway
  evidence_type: NAS
  original_reference_id: PMID:33737461
  review:
    summary: NAS annotation for cytokine-mediated signaling pathway from 
      ComplexPortal.
    action: ACCEPT
    reason: IL-10 is a cytokine that mediates signaling through its receptor. 
      This is a core annotation that is well-supported (deep research review).
    supported_by:
    - reference_id: PMID:33737461
      supporting_text: Interleukin-10 (IL-10) is an immunoregulatory cytokine 
        with both anti-inflammatory and immunostimulatory properties and is 
        frequently dysregulated in disease.
- term:
    id: GO:0042531
    label: positive regulation of tyrosine phosphorylation of STAT protein
  evidence_type: NAS
  original_reference_id: PMID:16982608
  review:
    summary: NAS annotation for positive regulation of STAT tyrosine 
      phosphorylation from PMID:16982608.
    action: ACCEPT
    reason: IL-10 signaling leads to JAK1/TYK2-mediated tyrosine phosphorylation
      of STAT3, which is the canonical downstream signaling event. This is a 
      core mechanistic annotation (PMID:16982608, deep research review).
    supported_by:
    - reference_id: PMID:16982608
      supporting_text: The basic mechanistic features of the assembly process 
        are likely shared by six additional class-2 cytokines (viral IL-10s, 
        IL-22, IL-26, IL-28A, IL28B, and IL-29) to promote IL-10R2 binding to 
        six additional receptor complexes.
- term:
    id: GO:0050728
    label: negative regulation of inflammatory response
  evidence_type: NAS
  original_reference_id: PMID:31611251
  review:
    summary: NAS annotation for negative regulation of inflammatory response 
      from ComplexPortal.
    action: ACCEPT
    reason: Anti-inflammatory activity is the core function of IL-10. Multiple 
      evidence codes support this annotation (IBA, IDA, NAS from multiple 
      sources).
    supported_by:
    - reference_id: PMID:31611251
      supporting_text: The cytokine IL-10 is a key anti-inflammatory mediator 
        ensuring protection of a host from over-exuberant responses to pathogens
        and microbiota
- term:
    id: GO:0050728
    label: negative regulation of inflammatory response
  evidence_type: NAS
  original_reference_id: PMID:21857966
  review:
    summary: NAS annotation for negative regulation of inflammatory response 
      from PMID:21857966, which is about WNT5A signaling and neuroinflammation.
    action: ACCEPT
    reason: While PMID:21857966 is primarily about WNT5A, IL-10 is mentioned as 
      an anti-inflammatory cytokine in the context of neuroinflammation. The 
      annotation itself is correct regardless of the reference context.
    supported_by:
    - reference_id: PMID:21857966
      supporting_text: We found that IL-10, a prototypic anti-inflammatory 
        cytokine, caused concentration-dependent rescue effects on Aβ toxicity
- term:
    id: GO:0034115
    label: negative regulation of heterotypic cell-cell adhesion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation transferred from mouse Il10 (P18893) for negative 
      regulation of heterotypic cell-cell adhesion. IL-10 downregulates adhesion
      molecules.
    action: KEEP_AS_NON_CORE
    reason: IL-10 downregulates ICAM-1 and other adhesion molecules on monocytes
      (PMID:7512027 per UniProt), which affects cell-cell adhesion. Transfer 
      from mouse Il10 is reasonable. Keep as non-core.
- term:
    id: GO:0034116
    label: positive regulation of heterotypic cell-cell adhesion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation transferred from FasL/TNFSF6 (P06804) for positive 
      regulation of heterotypic cell-cell adhesion. This is an inappropriate 
      transfer.
    action: REMOVE
    reason: This annotation was transferred from FasL (TNFSF6, P06804), which is
      a death ligand in the TNF superfamily. IL-10 is an anti-inflammatory 
      cytokine in the IL-10 family. These proteins are functionally very 
      different and the transfer is inappropriate. FasL mediates apoptotic and 
      adhesion effects through completely different mechanisms than IL-10.
- term:
    id: GO:0045930
    label: negative regulation of mitotic cell cycle
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation transferred from FasL/TNFSF6 (P06804). Inappropriate
      transfer.
    action: REMOVE
    reason: Transfer from FasL (P06804) is inappropriate. FasL-mediated cell 
      cycle arrest is related to its death receptor signaling, which has no 
      mechanistic parallel in IL-10 biology.
- term:
    id: GO:0072577
    label: endothelial cell apoptotic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation transferred from FasL/TNFSF6 (P06804). Inappropriate
      transfer.
    action: REMOVE
    reason: Transfer from FasL (P06804) is inappropriate. FasL induces apoptosis
      through Fas receptor engagement, which is mechanistically unrelated to 
      IL-10 function. IL-10 is generally anti-apoptotic, not pro-apoptotic.
- term:
    id: GO:1904706
    label: negative regulation of vascular associated smooth muscle cell 
      proliferation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation transferred from mouse Il10 (P18893). IL-10 may 
      inhibit vascular smooth muscle cell proliferation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Transfer from mouse Il10 (P18893) is reasonable in principle, but 
      regulation of vascular smooth muscle cell proliferation is a peripheral 
      non-immune effect. Over-annotation for this immune cytokine.
- term:
    id: GO:1904707
    label: positive regulation of vascular associated smooth muscle cell 
      proliferation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation transferred from FasL/TNFSF6 (P06804). Inappropriate
      transfer.
    action: REMOVE
    reason: Transfer from FasL (P06804) is inappropriate. The functional 
      mechanisms of FasL and IL-10 are completely different, and the vascular 
      smooth muscle proliferation effects of FasL cannot be transferred to 
      IL-10.
- term:
    id: GO:0008285
    label: negative regulation of cell population proliferation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation transferred from mouse Il10 (P18893). IL-10 can 
      inhibit proliferation of certain cell types.
    action: KEEP_AS_NON_CORE
    reason: IL-10 can inhibit T cell proliferation (PMID:8499633) and has 
      anti-proliferative effects on certain cell types. Transfer from mouse Il10
      is reasonable. Keep as non-core.
- term:
    id: GO:1903034
    label: regulation of response to wounding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation transferred from mouse Il10 (P18893). IL-10 
      modulates wound healing through anti-inflammatory effects.
    action: KEEP_AS_NON_CORE
    reason: IL-10 modulates wound healing responses through its 
      anti-inflammatory properties. Transfer from mouse Il10 is reasonable. Keep
      as non-core.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-449803
  review:
    summary: TAS annotation for extracellular region from Reactome (IL10 dimer 
      binds IL10RA:JAK1). IL-10 is a secreted protein.
    action: ACCEPT
    reason: IL-10 is secreted and localizes to the extracellular region where it
      binds its receptor complex. Reactome pathway annotation is consistent with
      known biology.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-449811
  review:
    summary: TAS for extracellular region from Reactome (IL10 
      dimer:2xIL10RA1:JAK1 binds IL10RB:TYK2).
    action: ACCEPT
    reason: Same as above. IL-10 is extracellular. Reactome annotation 
      consistent with known biology.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-449855
  review:
    summary: TAS for extracellular region from Reactome (IL10 dimerizes).
    action: ACCEPT
    reason: IL-10 dimerizes in the extracellular space. Correct annotation.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6784006
  review:
    summary: TAS for extracellular region from Reactome (STAT3 phosphorylation 
      by JAK1/TYK2).
    action: ACCEPT
    reason: IL-10 is the extracellular ligand in this signaling event. Correct.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6784319
  review:
    summary: TAS for extracellular region from Reactome (JAK1,TYK2 
      phosphorylation).
    action: ACCEPT
    reason: IL-10 is extracellular during this signaling step. Correct.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6784323
  review:
    summary: TAS for extracellular region from Reactome (receptor complex binds 
      STAT3).
    action: ACCEPT
    reason: IL-10 remains in the extracellular region bound to its receptor. 
      Correct.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6784324
  review:
    summary: TAS for extracellular region from Reactome (IL10RA 
      phosphorylation).
    action: ACCEPT
    reason: IL-10 is extracellular in this signaling context. Correct.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6784791
  review:
    summary: TAS for extracellular region from Reactome (STAT3 dissociation from
      receptor).
    action: ACCEPT
    reason: IL-10 is extracellular. Correct.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6789615
  review:
    summary: TAS for extracellular region from Reactome (STAT3-upregulated 
      extracellular protein expression).
    action: ACCEPT
    reason: IL-10 is extracellular. Correct.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8981073
  review:
    summary: TAS for extracellular region from Reactome (Expression of 
      Interleukin-10).
    action: ACCEPT
    reason: IL-10 is expressed and secreted to the extracellular region. 
      Correct.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9664346
  review:
    summary: TAS for extracellular region from Reactome (IL10 gene produces IL10
      protein).
    action: ACCEPT
    reason: IL-10 is a secreted extracellular protein. Correct.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IDA
  original_reference_id: PMID:21323571
  review:
    summary: IDA for extracellular space from PMID:21323571, which studied 
      cytokines in premature coronary artery disease patients.
    action: ACCEPT
    reason: IL-10 is detected in the extracellular space (serum/plasma) of 
      patients. Consistent with IL-10 being a secreted cytokine.
    supported_by:
    - reference_id: PMID:21323571
      supporting_text: Serum IL-10, IL-18, and TNF-alpha were measured using 
        enzyme-linked immunosorbent assay
- term:
    id: GO:0032692
    label: negative regulation of interleukin-1 production
  evidence_type: TAS
  original_reference_id: PMID:19262501
  review:
    summary: TAS annotation for negative regulation of IL-1 production from 
      PMID:19262501, about regulatory B cells in sheep Peyer's patches that 
      secrete IL-10 and downregulate TLR9-induced cytokine responses.
    action: ACCEPT
    reason: IL-10 inhibition of IL-1 production is well-established as part of 
      its core anti-inflammatory function. The original CSIF description 
      (PMID:1940799) showed IL-10 inhibits multiple pro-inflammatory cytokines. 
      PMID:19262501 provides additional evidence from Peyer's patch B cells.
    supported_by:
    - reference_id: PMID:19262501
      supporting_text: A novel regulatory B-cell population in sheep Peyer's 
        patches spontaneously secretes IL-10 and downregulates TLR9-induced 
        IFNalpha responses.
- term:
    id: GO:0032695
    label: negative regulation of interleukin-12 production
  evidence_type: TAS
  original_reference_id: PMID:19262501
  review:
    summary: TAS for negative regulation of IL-12 production from PMID:19262501.
    action: ACCEPT
    reason: IL-10 inhibition of IL-12 production by monocytes/macrophages and 
      dendritic cells is one of its most important anti-inflammatory activities.
      IL-12 suppression is critical for limiting Th1 responses (PMID:19262501, 
      deep research review).
    supported_by:
    - reference_id: PMID:19262501
      supporting_text: Neutralization of the IL-10 or depletion of CD21(+) B 
        cells resulted in a significant increase in CpG-induced 
        IFNalpha-response in PPs, suggesting that IL-10 from B cells regulate 
        innate responses in PPs.
- term:
    id: GO:0032701
    label: negative regulation of interleukin-18 production
  evidence_type: TAS
  original_reference_id: PMID:19262501
  review:
    summary: TAS for negative regulation of IL-18 production from PMID:19262501.
    action: ACCEPT
    reason: IL-10 suppression of IL-18 production is consistent with its broad 
      anti-inflammatory activity. IL-18 is a pro-inflammatory cytokine that 
      IL-10 is known to suppress (PMID:19262501).
    supported_by:
    - reference_id: PMID:19262501
      supporting_text: PP cells spontaneously secreted high levels of IL-10, and
        the primary source of the IL-10 was resting CD5(-)CD11c(-)CD21(+) B 
        cells.
- term:
    id: GO:0032715
    label: negative regulation of interleukin-6 production
  evidence_type: TAS
  original_reference_id: PMID:19262501
  review:
    summary: TAS for negative regulation of IL-6 production from PMID:19262501.
    action: ACCEPT
    reason: IL-10 inhibition of IL-6 production is well-established and also 
      supported by IDA annotation from PMID:10443688 (PMID:19262501).
    supported_by:
    - reference_id: PMID:19262501
      supporting_text: PP cells spontaneously secreted high levels of IL-10, and
        the primary source of the IL-10 was resting CD5(-)CD11c(-)CD21(+) B 
        cells.
- term:
    id: GO:0032717
    label: negative regulation of interleukin-8 production
  evidence_type: TAS
  original_reference_id: PMID:19262501
  review:
    summary: TAS for negative regulation of IL-8 production from PMID:19262501.
    action: ACCEPT
    reason: IL-10 inhibition of IL-8 (CXCL8) production is part of its broad 
      suppression of pro-inflammatory mediators (PMID:19262501).
    supported_by:
    - reference_id: PMID:19262501
      supporting_text: PP cells spontaneously secreted high levels of IL-10, and
        the primary source of the IL-10 was resting CD5(-)CD11c(-)CD21(+) B 
        cells.
- term:
    id: GO:0032720
    label: negative regulation of tumor necrosis factor production
  evidence_type: TAS
  original_reference_id: PMID:19262501
  review:
    summary: TAS for negative regulation of TNF production from PMID:19262501.
    action: ACCEPT
    reason: IL-10 suppression of TNF production is one of the earliest and best 
      characterized functions of IL-10 (PMID:1940799, PMID:19262501).
    supported_by:
    - reference_id: PMID:19262501
      supporting_text: A novel regulatory B-cell population in sheep Peyer's 
        patches spontaneously secretes IL-10 and downregulates TLR9-induced 
        IFNalpha responses.
- term:
    id: GO:0071650
    label: negative regulation of chemokine (C-C motif) ligand 5 production
  evidence_type: TAS
  original_reference_id: PMID:19262501
  review:
    summary: TAS for negative regulation of CCL5 (RANTES) production from 
      PMID:19262501.
    action: ACCEPT
    reason: IL-10 suppression of chemokine production including CCL5/RANTES is 
      consistent with its broad anti-inflammatory activity (PMID:19262501).
    supported_by:
    - reference_id: PMID:19262501
      supporting_text: These IL-10-secreting PP B cells may represent a novel 
        subset of the recently proposed regulatory B cells (B(regs)) in the 
        intestine.
- term:
    id: GO:1903659
    label: regulation of complement-dependent cytotoxicity
  evidence_type: IMP
  original_reference_id: PMID:16034134
  negated: true
  review:
    summary: 'NOT annotation: IL-10 does NOT regulate complement-dependent cytotoxicity
      based on PMID:16034134.'
    action: ACCEPT
    reason: This is a NOT annotation indicating IL-10 was tested and found not 
      to regulate complement-dependent cytotoxicity. Negative results are 
      informative and should be retained.
    supported_by:
    - reference_id: PMID:16034134
      supporting_text: porcine EC incubated with IL-4 or IL-13, but not with 
        IL-10 or IL-11, became protected from killing by complement and 
        apoptosis induced by TNF-alpha plus cycloheximide.
- term:
    id: GO:2000352
    label: negative regulation of endothelial cell apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:16034134
  negated: true
  review:
    summary: 'NOT annotation: IL-10 does NOT negatively regulate endothelial cell
      apoptotic process based on PMID:16034134.'
    action: ACCEPT
    reason: This is a NOT annotation indicating IL-10 was tested and found not 
      to inhibit endothelial cell apoptosis. Negative results are informative.
    supported_by:
    - reference_id: PMID:16034134
      supporting_text: porcine EC incubated with IL-4 or IL-13, but not with 
        IL-10 or IL-11, became protected from killing by complement and 
        apoptosis induced by TNF-alpha plus cycloheximide.
- term:
    id: GO:0042130
    label: negative regulation of T cell proliferation
  evidence_type: NAS
  original_reference_id: PMID:14971032
  review:
    summary: NAS for negative regulation of T cell proliferation from 
      PMID:14971032. IL-10 upregulates LIR-2 on DCs, causing T cell 
      hyporesponsiveness.
    action: ACCEPT
    reason: IL-10 inhibition of T cell proliferation is well-documented. 
      PMID:14971032 showed IL-10 regulates LIR-2 on dendritic cells resulting in
      T cell hyporesponsiveness. Also supported by PMID:8499633 which showed 
      direct inhibition of T cell growth.
    supported_by:
    - reference_id: PMID:14971032
      supporting_text: Interleukin 10 regulates cell surface and soluble LIR-2 
        (CD85d) expression on dendritic cells resulting in T cell 
        hyporesponsiveness in vitro.
    - reference_id: PMID:8499633
      supporting_text: Human interleukin-10 (IL-10) inhibits T-cell 
        proliferation and cytokine production in the presence of monocytes.
- term:
    id: GO:0071222
    label: cellular response to lipopolysaccharide
  evidence_type: NAS
  original_reference_id: PMID:14971032
  review:
    summary: NAS for cellular response to LPS from PMID:14971032. IL-10 
      modulates the response to LPS.
    action: KEEP_AS_NON_CORE
    reason: IL-10 modulates the cellular response to LPS stimulation by 
      suppressing pro-inflammatory cytokine production. This is a 
      stimulus-response context for IL-10 function. Keep as non-core.
    supported_by:
    - reference_id: PMID:14971032
      supporting_text: LPS-stimulated, LIR-2-transfected DC inhibited the 
        proliferation of T cells in autologous, as well as allogeneic culture 
        systems in vitro.
- term:
    id: GO:0060302
    label: negative regulation of cytokine activity
  evidence_type: IMP
  original_reference_id: PMID:9847016
  review:
    summary: IMP annotation for negative regulation of cytokine activity from 
      PMID:9847016. IL-10 suppresses cytokine activity as part of its 
      anti-inflammatory program.
    action: ACCEPT
    reason: IL-10 negatively regulates the activity of multiple pro-inflammatory
      cytokines. This is consistent with its core anti-inflammatory function.
    supported_by:
    - reference_id: PMID:9847016
      supporting_text: Preincubation of LPS-stimulated peritoneal macrophages 
        with rhuIL-10 caused significant (P<0.05) reduction in secretion of TNF,
        IL-6, and PGE2, in a dose-dependent manner.
- term:
    id: GO:0002904
    label: positive regulation of B cell apoptotic process
  evidence_type: IDA
  original_reference_id: PMID:9184696
  review:
    summary: 'IDA for positive regulation of B cell apoptotic process from PMID:9184696.
      This paper showed dual effects of IL-10 on SAC-activated B cells: promoting
      apoptosis at the initiation of activation and proliferation after pre-activation.'
    action: KEEP_AS_NON_CORE
    reason: PMID:9184696 demonstrated that IL-10 has dual effects on B cells 
      depending on activation state. IL-10 induces apoptosis in B cells at early
      stages of activation while promoting survival/proliferation of 
      pre-activated B cells. The pro-apoptotic effect is context-dependent and 
      not a core function.
    supported_by:
    - reference_id: PMID:9184696
      supporting_text: The apoptosis and proliferation of SAC-activated B cells 
        by IL-10 are associated with changes in Bcl-2, Bcl-xL, and Mcl-1 
        expression.
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IDA
  original_reference_id: PMID:9184696
  review:
    summary: IDA for regulation of gene expression from PMID:9184696. IL-10 
      treatment altered expression of Bcl-2, Bcl-xL, and Mcl-1 in B cells.
    action: KEEP_AS_NON_CORE
    reason: IL-10 does regulate gene expression through STAT3 signaling. This is
      a very broad term; the specific gene expression changes (Bcl-2 family 
      members) are context-specific to the B cell activation study 
      (PMID:9184696). Keep as non-core.
    supported_by:
    - reference_id: PMID:9184696
      supporting_text: The apoptosis and proliferation of SAC-activated B cells 
        by IL-10 are associated with changes in Bcl-2, Bcl-xL, and Mcl-1 
        expression.
- term:
    id: GO:0030889
    label: negative regulation of B cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:9184696
  review:
    summary: IDA for negative regulation of B cell proliferation from 
      PMID:9184696. Context-dependent effect of IL-10 on B cell proliferation.
    action: KEEP_AS_NON_CORE
    reason: PMID:9184696 showed that IL-10 can inhibit B cell proliferation 
      depending on the activation state of the B cells. This is a real but 
      context-dependent effect. Keep as non-core.
    supported_by:
    - reference_id: PMID:9184696
      supporting_text: The apoptosis and proliferation of SAC-activated B cells 
        by IL-10 are associated with changes in Bcl-2, Bcl-xL, and Mcl-1 
        expression.
- term:
    id: GO:0051045
    label: negative regulation of membrane protein ectodomain proteolysis
  evidence_type: IDA
  original_reference_id: PMID:18383040
  review:
    summary: IDA for negative regulation of membrane protein ectodomain 
      proteolysis from PMID:18383040. IL-10 may inhibit shedding of certain 
      membrane proteins.
    action: KEEP_AS_NON_CORE
    reason: PMID:18383040 showed IL-10 inhibits TACE/ADAM-17 activity on 
      monocytes, which regulates TNF-alpha shedding. This is a downstream effect
      of IL-10 anti-inflammatory signaling. Keep as non-core.
    supported_by:
    - reference_id: PMID:18383040
      supporting_text: In the presence of IL-10, TNF-alpha production and 
        activation of surface TACE was significantly inhibited.
- term:
    id: GO:0001819
    label: positive regulation of cytokine production
  evidence_type: IDA
  original_reference_id: PMID:10443688
  review:
    summary: IDA for positive regulation of cytokine production from 
      PMID:10443688. IL-10 can positively regulate production of certain 
      cytokines while suppressing others.
    action: KEEP_AS_NON_CORE
    reason: While IL-10 is primarily known as an inhibitor of pro-inflammatory 
      cytokines, it can promote production of certain cytokines (e.g., it can 
      enhance IL-1RA production). This dual activity is consistent with IL-10 
      biology. Keep as non-core since the primary function is anti-inflammatory.
    supported_by:
    - reference_id: PMID:10443688
      supporting_text: its effect on IL-10 secretion was biphasic, producing 
        stimulation at lower, and inhibition at higher doses.
- term:
    id: GO:0002719
    label: negative regulation of cytokine production involved in immune 
      response
  evidence_type: IDA
  original_reference_id: PMID:10443688
  review:
    summary: IDA for negative regulation of cytokine production in immune 
      response from PMID:10443688.
    action: ACCEPT
    reason: This is a core function of IL-10. It specifically captures the 
      immune context of IL-10's cytokine-suppressive activity. More specific 
      than the general negative regulation of cytokine production (GO:0001818) 
      and directly relevant to IL-10's primary role.
    supported_by:
    - reference_id: PMID:10443688
      supporting_text: Dexamethasone had different effects on LPS-induced 
        TNFalpha and IL-10 secretion; whereas it suppressed TNFalpha in a 
        dose-dependent fashion
- term:
    id: GO:0005125
    label: cytokine activity
  evidence_type: NAS
  original_reference_id: PMID:10443688
  review:
    summary: NAS for cytokine activity from PMID:10443688. Redundant with IBA 
      and IDA annotations.
    action: ACCEPT
    reason: Cytokine activity is the core molecular function. Multiple evidence 
      codes support this annotation.
    supported_by:
    - reference_id: PMID:10443688
      supporting_text: interleukin (IL)-10 (an anti-inflammatory cytokine)
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IDA
  original_reference_id: PMID:10443688
  review:
    summary: IDA for extracellular space from PMID:10443688.
    action: ACCEPT
    reason: IL-10 is secreted and found in the extracellular space. 
      Well-established.
    supported_by:
    - reference_id: PMID:10443688
      supporting_text: the sensitivity of these cells to glucocorticoids is 
        altered by TNFalpha or IL-10 pretreatment
- term:
    id: GO:0032715
    label: negative regulation of interleukin-6 production
  evidence_type: IDA
  original_reference_id: PMID:10443688
  review:
    summary: IDA for negative regulation of IL-6 production from PMID:10443688.
    action: ACCEPT
    reason: IL-10 suppression of IL-6 production is a well-characterized core 
      anti-inflammatory activity. Also supported by TAS from PMID:19262501.
    supported_by:
    - reference_id: PMID:10443688
      supporting_text: with IL-10 improved, the ability of dexamethasone to 
        suppress IL-6 secretion in whole-blood cell cultures
- term:
    id: GO:0051384
    label: response to glucocorticoid
  evidence_type: IDA
  original_reference_id: PMID:10443688
  review:
    summary: IDA for response to glucocorticoid from PMID:10443688. IL-10 
      expression is regulated by glucocorticoids.
    action: KEEP_AS_NON_CORE
    reason: Glucocorticoid regulation of IL-10 expression is documented but 
      describes regulation of IL-10 rather than a core function of IL-10 itself.
      Keep as non-core.
    supported_by:
    - reference_id: PMID:10443688
      supporting_text: IL-10 increased (P < 0.001), the concentration of 
        dexamethasone binding sites in these cells
- term:
    id: GO:0002237
    label: response to molecule of bacterial origin
  evidence_type: IDA
  original_reference_id: PMID:17449476
  review:
    summary: IDA for response to molecule of bacterial origin from 
      PMID:17449476. IL-10 is produced in response to bacterial products.
    action: KEEP_AS_NON_CORE
    reason: IL-10 production is induced by bacterial products as part of the 
      immune response regulatory feedback loop. This describes a context for 
      IL-10 induction rather than a core function. Keep as non-core.
    supported_by:
    - reference_id: PMID:17449476
      supporting_text: there is increased production of interferon-gamma and 
        interleukin-10, which indicates that immunity in response to Eis 
        treatment is skewed away from a protective T(H)1 response
- term:
    id: GO:0030595
    label: leukocyte chemotaxis
  evidence_type: TAS
  original_reference_id: PMID:9405662
  review:
    summary: TAS for leukocyte chemotaxis from PMID:9405662. This paper 
      identified functional domains on human IL-10 (also referenced for protein 
      sequence in UniProt).
    action: KEEP_AS_NON_CORE
    reason: IL-10 can modulate leukocyte chemotaxis through its effects on 
      chemokine production and adhesion molecule expression. PMID:9405662 
      studied functional domains of IL-10 including chemotactic effects. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:9405662
      supporting_text: IL-10 significantly affects chemokine biology, because 
        human IL-10 inhibits chemokine production and is a specific chemotactic 
        factor for CD8+ T cells.
- term:
    id: GO:0030183
    label: B cell differentiation
  evidence_type: NAS
  original_reference_id: PMID:8228801
  review:
    summary: NAS for B cell differentiation from PMID:8228801. IL-10 promotes B 
      cell differentiation.
    action: KEEP_AS_NON_CORE
    reason: IL-10 promotes B cell differentiation, particularly plasma cell 
      differentiation. This is a well-established but non-core function of IL-10
      (PMID:8228801, PMID:9184696).
    supported_by:
    - reference_id: PMID:8228801
      supporting_text: Interleukin 10 (IL-10) has recently been shown to induce 
        normal human B lymphocytes to proliferate and differentiate into 
        immunoglobulin (Ig)-secreting cells.
- term:
    id: GO:0042100
    label: B cell proliferation
  evidence_type: NAS
  original_reference_id: PMID:8228801
  review:
    summary: NAS for B cell proliferation from PMID:8228801. IL-10 promotes B 
      cell proliferation in certain contexts.
    action: KEEP_AS_NON_CORE
    reason: IL-10 was originally identified as a B cell growth factor as well as
      a cytokine synthesis inhibitor. It promotes B cell proliferation of 
      pre-activated B cells (PMID:8228801, PMID:9184696). Keep as non-core.
    supported_by:
    - reference_id: PMID:8228801
      supporting_text: IL-2 and IL-10 were found to synergize to induce the 
        proliferation and differentiation of B-CLL cells.
- term:
    id: GO:0045191
    label: regulation of isotype switching
  evidence_type: NAS
  original_reference_id: PMID:8228801
  review:
    summary: NAS for regulation of isotype switching from PMID:8228801. IL-10 
      regulates immunoglobulin isotype switching in B cells.
    action: KEEP_AS_NON_CORE
    reason: IL-10 is known to regulate immunoglobulin isotype switching, 
      promoting certain isotype classes. This is a real but non-core function 
      related to IL-10's effects on B cells (PMID:8228801).
    supported_by:
    - reference_id: PMID:8228801
      supporting_text: normal B cells which proliferated strongly and secreted 
        large amounts of IgM, IgG, and IgA.
- term:
    id: GO:0005141
    label: interleukin-10 receptor binding
  evidence_type: NAS
  original_reference_id: PMID:1847510
  review:
    summary: NAS for IL-10 receptor binding from PMID:1847510. This is the 
      seminal paper on IL-10 cDNA cloning (Vieira et al., 1991).
    action: ACCEPT
    reason: IL-10 receptor binding is a core molecular function. PMID:1847510 is
      the original cloning paper for human IL-10 (Vieira et al., PNAS 1991) and 
      established IL-10 as a ligand for its receptor.
    supported_by:
    - reference_id: PMID:1847510
      supporting_text: cDNA clones encoding human IL-10 (hIL-10) were isolated 
        from a tetanus toxin-specific human T-cell clone.
- term:
    id: GO:0008083
    label: growth factor activity
  evidence_type: NAS
  original_reference_id: PMID:1371884
  review:
    summary: NAS for growth factor activity from PMID:1371884. IL-10 was early 
      on characterized as having growth factor-like activity on B cells.
    action: MODIFY
    reason: While IL-10 does have proliferation-promoting effects on certain 
      cell types (B cells, mast cells), it is more accurately classified as a 
      cytokine than a growth factor. The term "cytokine activity" (GO:0005125) 
      is more appropriate. Growth factor activity implies a more general 
      proliferative function that does not capture IL-10's primary 
      immunomodulatory role.
    proposed_replacement_terms:
    - id: GO:0005125
      label: cytokine activity
    supported_by:
    - reference_id: PMID:1371884
      supporting_text: human and viral IL-10 stimulate DNA replication of B 
        lymphocytes activated either via their antigen receptor or via their 
        CD40 antigen.
- term:
    id: GO:0030097
    label: hemopoiesis
  evidence_type: TAS
  original_reference_id: PMID:11244051
  review:
    summary: TAS for hemopoiesis from PMID:11244051. IL-10 has effects on 
      hematopoietic cell development.
    action: KEEP_AS_NON_CORE
    reason: IL-10 has effects on hematopoietic cell development and 
      differentiation, particularly on monocyte/macrophage and B cell lineages. 
      This is a broad term but represents a real function. Keep as non-core.
    supported_by:
    - reference_id: PMID:11244051
      supporting_text: multifunctional cytokine with diverse effects on most 
        hemopoietic cell types.
- term:
    id: GO:0032687
    label: negative regulation of interferon-alpha production
  evidence_type: NAS
  original_reference_id: PMID:9637497
  review:
    summary: NAS for negative regulation of IFN-alpha production from 
      PMID:9637497. This paper demonstrated that IL-10 reduces 
      IFN-alpha-producing cells and bulk IFN-alpha in response to viral 
      stimulation.
    action: ACCEPT
    reason: PMID:9637497 directly demonstrated that IL-10 suppresses IFN-alpha 
      production by PBMCs in response to multiple viruses (HSV-1, Sendai virus, 
      NDV, VSV). This is a specific and well-documented anti-inflammatory 
      function of IL-10.
    supported_by:
    - reference_id: PMID:9637497
      supporting_text: Human IL-10 (hIL-10) caused reductions in both the 
        frequency of IFN-alpha-producing cells (IPC) and bulk IFN in response to
        herpes simplex virus type-1 (HSV-1), Sendai virus, Newcastle disease 
        virus, and vesicular stomatitis virus.
- term:
    id: GO:0042092
    label: type 2 immune response
  evidence_type: TAS
  original_reference_id: PMID:11244051
  review:
    summary: TAS for type 2 immune response from PMID:11244051. IL-10 is 
      associated with Th2/type 2 immune responses.
    action: KEEP_AS_NON_CORE
    reason: IL-10 was originally identified as a Th2-derived cytokine and is 
      associated with type 2 immune responses. However, IL-10 is now known to be
      produced by diverse immune cell types, not exclusively Th2 cells. The 
      association with type 2 immunity is a non-core aspect of IL-10 biology.
    supported_by:
    - reference_id: PMID:11244051
      supporting_text: IL-10 plays a key role in differentiation and function of
        a newly appreciated type of T cell, the T regulatory cell, which may 
        figure prominently in control of immune responses and tolerance in vivo.
- term:
    id: GO:0042130
    label: negative regulation of T cell proliferation
  evidence_type: NAS
  original_reference_id: PMID:8499633
  review:
    summary: NAS for negative regulation of T cell proliferation from 
      PMID:8499633, which directly demonstrated that IL-10 inhibits T cell 
      growth.
    action: ACCEPT
    reason: PMID:8499633 showed that IL-10 directly inhibits T cell growth 
      (55.4% inhibition) when stimulated with immobilized anti-CD3, even in the 
      absence of monocytes. This establishes a direct effect on T cells.
    supported_by:
    - reference_id: PMID:8499633
      supporting_text: highly purified peripheral blood T cells containing less 
        than 0.1% CD14+ cells and unresponsive to phytohemagglutinin (PHA), were
        growth-inhibited by IL-10 when stimulated with immobilized OKT3 
        monoclonal antibody (MoAb; 55.4% inhibition).
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: NAS
  original_reference_id: PMID:8312229
  review:
    summary: NAS for negative regulation of apoptotic process from PMID:8312229,
      which showed IL-10 inhibits apoptotic cell death in T cells starved of 
      IL-2.
    action: KEEP_AS_NON_CORE
    reason: PMID:8312229 demonstrated that IL-10 inhibits apoptosis in 
      IL-2-deprived T cells. This is a real but context-dependent anti-apoptotic
      effect of IL-10. Keep as non-core.
    supported_by:
    - reference_id: PMID:8312229
      supporting_text: IL-10 inhibits apoptotic cell death in human T cells 
        starved of IL-2.
- term:
    id: GO:0045347
    label: negative regulation of MHC class II biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:11244051
  review:
    summary: TAS for negative regulation of MHC class II biosynthesis from 
      PMID:11244051.
    action: ACCEPT
    reason: IL-10 downregulation of MHC class II expression is a core function, 
      also supported by IDA from PMID:1940799 (PMID:11244051, PMID:1940799).
    supported_by:
    - reference_id: PMID:11244051
      supporting_text: IL-10 regulates growth and/or differentiation of B cells,
        NK cells, cytotoxic and helper T cells, mast cells, granulocytes, 
        dendritic cells, keratinocytes, and endothelial cells.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IPI
  original_reference_id: PMID:33737461
  review:
    summary: IPI for extracellular region from PMID:33737461 (ComplexPortal).
    action: ACCEPT
    reason: IL-10 is a secreted protein found in the extracellular region. 
      Correct.
    supported_by:
    - reference_id: PMID:33737461
      supporting_text: We used a structure-based approach to deconvolute IL-10 
        pleiotropy by determining the structure of the IL-10 receptor (IL-10R) 
        complex by cryo-electron microscopy at a resolution of 3.5 angstroms.
- term:
    id: GO:0045063
    label: T-helper 1 cell differentiation
  evidence_type: IDA
  original_reference_id: PMID:33737461
  review:
    summary: IDA for T-helper 1 cell differentiation from PMID:33737461 
      (ComplexPortal). IL-10 can influence Th1/Th2 balance.
    action: KEEP_AS_NON_CORE
    reason: IL-10 can influence T helper cell differentiation, particularly by 
      suppressing Th1 differentiation through inhibition of IL-12 and IFN-gamma 
      production. The annotation says Th1 differentiation, not inhibition of it,
      so the qualifier from the GOA should be checked. Keep as non-core.
    supported_by:
    - reference_id: PMID:33737461
      supporting_text: Some variants displayed myeloid-biased activity by 
        suppressing macrophage activation without stimulating inflammatory CD8+ 
        T cells, thereby uncoupling the major opposing functions of IL-10.
- term:
    id: GO:0002639
    label: positive regulation of immunoglobulin production
  evidence_type: IGI
  original_reference_id: PMID:22962438
  review:
    summary: IGI for positive regulation of immunoglobulin production from 
      PMID:22962438, with genetic interaction with IL-6 (P60568).
    action: KEEP_AS_NON_CORE
    reason: IL-10 promotes immunoglobulin production by B cells, often in 
      synergy with other cytokines like IL-6. This is consistent with IL-10's B 
      cell-stimulatory functions. Keep as non-core.
    supported_by:
    - reference_id: PMID:22962438
      supporting_text: CR1 inhibits the differentiation of B cells to 
        plasmablasts and their immunoglobulin production.
- term:
    id: GO:1900100
    label: positive regulation of plasma cell differentiation
  evidence_type: IGI
  original_reference_id: PMID:22962438
  review:
    summary: IGI for positive regulation of plasma cell differentiation from 
      PMID:22962438, with genetic interaction with IL-6 (P60568).
    action: KEEP_AS_NON_CORE
    reason: IL-10 promotes plasma cell differentiation, consistent with its B 
      cell stimulatory functions. Keep as non-core.
    supported_by:
    - reference_id: PMID:22962438
      supporting_text: CR1 inhibits the differentiation of B cells to 
        plasmablasts and their immunoglobulin production.
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to
    orthologs by curator judgment of sequence similarity
  findings:
  - statement: Some ISS annotations transfer from mouse Il10 (P18893) which is 
      appropriate, while others transfer from FasL/TNFSF6 (P06804) which is an 
      inappropriate source for IL-10 annotations due to completely different 
      function.
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
  - statement: IBA annotations for IL-10 are well-supported and represent core 
      functions.
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data
    to orthologs using Ensembl Compara
  findings:
  - statement: Many IEA transfers from rat Il10 (P29456) represent peripheral 
      observations (response to xenobiotic, activity, inactivity, carbon 
      monoxide, insulin, estradiol) that are over-annotations for human IL-10 
      core function.
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings:
  - statement: IEA annotations for core functions (cytokine activity, 
      extracellular space, immune response, TNF regulation) are correct.
- id: PMID:1940799
  title: "Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes."
  findings:
  - statement: Seminal paper establishing IL-10 as a cytokine synthesis 
      inhibitor.
    supporting_text: IL-10, added to monocytes, activated by interferon gamma 
      (IFN-gamma), LPS, or combinations of LPS and IFN-gamma at the onset of the
      cultures, strongly inhibited the production of IL-1 alpha, IL-1 beta, 
      IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF at the transcriptional level.
    reference_section_type: ABSTRACT
  - statement: Demonstrated inhibition of cytokine production and MHC class II 
      expression.
    supporting_text: IL-10, added to monocytes, activated by interferon gamma 
      (IFN-gamma), LPS, or combinations of LPS and IFN-gamma at the onset of the
      cultures, strongly inhibited the production of IL-1 alpha, IL-1 beta, 
      IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF at the transcriptional level.
    reference_section_type: ABSTRACT
- id: PMID:7749983
  title: Cross-linking of OX40 ligand, a member of the TNF/NGF cytokine family, 
    induces proliferation and differentiation in murine splenic B cells
  findings:
  - statement: This paper is about OX40L (TNFSF4), NOT about IL-10. Two IDA 
      annotations cite this paper for IL-10, which appears to be a reference 
      error.
    supporting_text: OX40 is a member of the TNF/NGF-receptor family expressed 
      on activated T cells, whose ligand is found on activated T and B cells.
    reference_section_type: ABSTRACT
- id: PMID:8312229
  title: IL-10 inhibits apoptotic cell death in human T cells starved of IL-2
  findings:
  - statement: IL-10 inhibits apoptosis in IL-2-deprived T cells.
    supporting_text: IL-10 inhibits apoptotic cell death in human T cells 
      starved of IL-2.
    reference_section_type: TITLE
- id: PMID:8499633
  title: Human interleukin-10 can directly inhibit T-cell growth
  findings:
  - statement: IL-10 directly inhibits T cell growth (55.4% inhibition with 
      anti-CD3).
    supporting_text: Highly purified peripheral blood T cells containing less 
      than 0.1% CD14+ cells and unresponsive to phytohemagglutinin (PHA), were 
      growth-inhibited by IL-10 when stimulated with immobilized OKT3 monoclonal
      antibody (MoAb; 55.4% inhibition).
    reference_section_type: ABSTRACT
  - statement: Effect is independent of monocytes.
    supporting_text: Thus, IL-10 can directly inhibit growth and IL-2 production
      in T cells triggered by immobilized OKT3 MoAb in the absence of monocytes.
    reference_section_type: ABSTRACT
- id: PMID:9184696
  title: The apoptosis and proliferation of SAC-activated B cells by IL-10 are 
    associated with changes in Bcl-2, Bcl-xL, and Mcl-1 expression
  findings:
  - statement: IL-10 has dual effects on B cells depending on activation state 
      -- apoptosis at initiation versus proliferation after pre-activation.
    supporting_text: the addition of IL-10 at the initiation of activation 
      down-regulated Bcl-xL, Bcl-2, and Mcl-1 expression. At the same time, B 
      cell proliferation was inhibited and apoptotic cell number increased, 
      suggesting the growth arrest and/or apoptosis of B cells.
    reference_section_type: ABSTRACT
  - statement: In contrast, IL-10 supported proliferation and differentiation of
      pre-activated B cells.
    supporting_text: In contrast, IL-10 failed to down-regulate the Bcl-xL and 
      Bcl-2 expression but rather augmented the expression of Mcl-1 of B cells 
      after preactivation for 48 hr with SAC and IL-2
    reference_section_type: ABSTRACT
- id: PMID:9637497
  title: Exogenous and endogenous IL-10 regulate IFN-alpha production by 
    peripheral blood mononuclear cells in response to viral stimulation
  findings:
  - statement: IL-10 reduces frequency of IFN-alpha-producing cells and bulk 
      IFN-alpha.
    supporting_text: Human IL-10 (hIL-10) caused reductions in both the 
      frequency of IFN-alpha-producing cells (IPC) and bulk IFN in response to 
      herpes simplex virus type-1 (HSV-1), Sendai virus, Newcastle disease 
      virus, and vesicular stomatitis virus.
    reference_section_type: ABSTRACT
  - statement: Effect seen with HSV-1, Sendai virus, NDV, and VSV stimulation.
    supporting_text: Human IL-10 (hIL-10) caused reductions in both the 
      frequency of IFN-alpha-producing cells (IPC) and bulk IFN in response to 
      herpes simplex virus type-1 (HSV-1), Sendai virus, Newcastle disease 
      virus, and vesicular stomatitis virus.
    reference_section_type: ABSTRACT
- id: PMID:10443688
  title: Tumor necrosis factor alpha decreases, and interleukin-10 increases, 
    the sensitivity of human monocytes to dexamethasone; potential regulation of
    the glucocorticoid receptor.
  findings:
  - statement: IL-10 increases the sensitivity of human monocytes to 
      dexamethasone and enhances glucocorticoid receptor concentration, 
      supporting IL-10 anti-inflammatory synergy with glucocorticoids.
    supporting_text: Pretreatment with TNFalpha diminished, and with IL-10 
      improved, the ability of dexamethasone to suppress IL-6 secretion in 
      whole-blood cell cultures (P < 0.01 for both) and to enhance IL-1 receptor
      antagonist secretion by U937 cells (P < 0.05 for both).
    reference_section_type: ABSTRACT
  - statement: IL-10 increased the concentration of dexamethasone binding sites 
      (glucocorticoid receptor) in monocytes.
    supporting_text: TNFalpha decreased (P < 0.001), while IL-10 increased (P < 
      0.001), the concentration of dexamethasone binding sites in these cells, 
      with no discernible effect on their binding affinity.
    reference_section_type: ABSTRACT
- id: PMID:14971032
  title: Interleukin 10 regulates cell surface and soluble LIR-2 (CD85d) 
    expression on dendritic cells resulting in T cell hyporesponsiveness in 
    vitro
  findings:
  - statement: IL-10 upregulates LIR-2 on DCs.
    supporting_text: the inhibitory receptor LIR-2 (leukocyte 
      immunoglobulin-like receptor-2, CD85d) is specifically up-regulated by 
      IL-10 on maturing human DC
    reference_section_type: ABSTRACT
  - statement: Results in T cell hyporesponsiveness.
    supporting_text: IL-10 renders DC hypostimulatory by up-regulating cell 
      surface LIR-2 and by inhibiting soluble LIR-2 in vitro
    reference_section_type: ABSTRACT
- id: PMID:16982608
  title: Conformational changes mediate interleukin-10 receptor 2 (IL-10R2) 
    binding to IL-10 and assembly of the signaling complex.
  findings:
  - statement: Key reference for IL-10 receptor interaction and JAK-STAT 
      signaling.
    supporting_text: Interleukin-10 receptor 2 (IL-10R2) is a critical component
      of the IL-10.IL-10R1.IL-10R2 complex which regulates IL-10-mediated 
      immunomodulatory responses
    reference_section_type: ABSTRACT
  - statement: Used for protein dimerization, receptor binding, and signaling 
      annotations.
    supporting_text: The ternary IL-10 signaling complex is assembled in a 
      sequential order with the IL-10.IL-10R1 interaction occurring first 
      followed by engagement of the IL-10R2 chain.
    reference_section_type: ABSTRACT
- id: PMID:19262501
  title: A novel regulatory B-cell population in sheep Peyer's patches 
    spontaneously secretes IL-10 and downregulates TLR9-induced IFNalpha 
    responses
  findings:
  - statement: B cells secrete IL-10 that suppresses multiple pro-inflammatory 
      cytokines.
    supporting_text: PP cells spontaneously secreted high levels of IL-10, and 
      the primary source of the IL-10 was resting CD5(-)CD11c(-)CD21(+) B cells.
    reference_section_type: ABSTRACT
  - statement: Supports TAS annotations for specific cytokine suppression.
    supporting_text: Neutralization of the IL-10 or depletion of CD21(+) B cells
      resulted in a significant increase in CpG-induced IFNalpha-response in 
      PPs, suggesting that IL-10 from B cells regulate innate responses in PPs.
    reference_section_type: ABSTRACT
- id: PMID:26962683
  title: IL10 inhibits starvation-induced autophagy in hypertrophic scar 
    fibroblasts via cross talk between the IL10-IL10R-STAT3 and IL10-AKT-mTOR 
    pathways
  findings:
  - statement: IL-10 inhibits autophagy via STAT3/AKT-mTOR crosstalk.
    supporting_text: IL10 inhibited starvation-induced autophagy and induced the
      expression of p-AKT and p-STAT3 in HSFs in a dose-dependent manner.
    reference_section_type: ABSTRACT
  - statement: Context-specific effect in hypertrophic scar fibroblasts.
    supporting_text: IL10 inhibits starvation-induced autophagy in hypertrophic 
      scar fibroblasts via cross talk between the IL10-IL10R-STAT3 and 
      IL10-AKT-mTOR pathways.
    reference_section_type: TITLE
- id: PMID:32296183
  title: A reference map of the human binary protein interactome
  findings:
  - statement: HuRI high-throughput Y2H screen.
    supporting_text: With approximately 53,000 protein-protein interactions, 
      HuRI has approximately four times as many such interactions as there are 
      high-quality curated interactions from small-scale studies.
    reference_section_type: ABSTRACT
  - statement: Interactions with keratins and other non-immune proteins are 
      likely false positives for a secreted cytokine.
    supporting_text: we expect HuRI to be depleted for PPIs that depend on 
      post-translational processing of human proteins that the yeast cell is 
      unable to catalyze or that require additional partners to stabilize the 
      interaction.
    reference_section_type: DISCUSSION
- id: PMID:11244051
  title: Interleukin-10 and the interleukin-10 receptor.
  findings:
  - statement: Referenced for hemopoiesis, type 2 immune response, and MHC class
      II regulation annotations.
    supporting_text: Interleukin-10 (IL-10), first recognized for its ability to
      inhibit activation and effector function of T cells, monocytes, and 
      macrophages, is a multifunctional cytokine with diverse effects on most 
      hemopoietic cell types.
    reference_section_type: ABSTRACT
- id: PMID:1847510
  title: "Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI."
  findings:
  - statement: Seminal paper cloning human IL-10 cDNA.
    supporting_text: cDNA clones encoding human IL-10 (hIL-10) were isolated 
      from a tetanus toxin-specific human T-cell clone.
    reference_section_type: ABSTRACT
- id: PMID:8228801
  title: Interleukin 10 (IL-10) upregulates functional high affinity IL-2 
    receptors on normal and leukemic B lymphocytes.
  findings:
  - statement: B cell differentiation, proliferation, and isotype switching 
      regulation by IL-10.
    supporting_text: Interleukin 10 (IL-10) has recently been shown to induce 
      normal human B lymphocytes to proliferate and differentiate into 
      immunoglobulin (Ig)-secreting cells.
    reference_section_type: ABSTRACT
- id: PMID:9405662
  title: Identification of functional domains on human interleukin 10
  findings:
  - statement: Mapped functional domains on IL-10 including chemotaxis-related 
      regions.
    supporting_text: human IL-10 inhibits chemokine production and is a specific
      chemotactic factor for CD8+ T cells
    reference_section_type: ABSTRACT
- id: Reactome:R-HSA-449803
  title: IL10 dimer binds IL10RA:JAK1
  findings: []
- id: Reactome:R-HSA-449811
  title: IL10 dimer:2xIL10RA1:JAK1 binds IL10RB:TYK2
  findings: []
- id: Reactome:R-HSA-449855
  title: IL10 dimerizes
  findings: []
- id: Reactome:R-HSA-6784006
  title: STAT3 is phosphorylated by p-Y-JAK1,P-Y-TYK2
  findings: []
- id: Reactome:R-HSA-6784319
  title: JAK1,TYK2 phosphorylate JAK1,TYK2
  findings: []
- id: Reactome:R-HSA-6784323
  title: IL10 dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2 binds STAT3
  findings: []
- id: Reactome:R-HSA-6784324
  title: p-Y-JAK1,p-Y-TYK2 phosphorylate IL10RA
  findings: []
- id: Reactome:R-HSA-6784791
  title: p-Y705-STAT3 dissociates from IL10 
    dimer:2xp-Y-IL10RA:p-Y-JAK1:2xIL10RB:p-Y-TYK2:p-Y705-STAT3
  findings: []
- id: Reactome:R-HSA-6789615
  title: Expression of STAT3-upregulated extracellular proteins
  findings: []
- id: Reactome:R-HSA-8981073
  title: Expression of Interleukin-10
  findings: []
- id: Reactome:R-HSA-9664346
  title: IL10 gene produces IL10 protein
  findings: []
- id: PMID:11485736
  title: Crystal structure of the IL-10/IL-10R1 complex reveals a shared 
    receptor binding site.
  findings:
  - statement: Structural basis of IL-10 binding to IL-10R1 (IL-10RA).
    supporting_text: Interleukin 10 (IL-10) is a dimeric cytokine that plays a 
      central role in suppressing inflammatory responses. These activities are 
      dependent on the interaction of IL-10 with its high-affinity receptor 
      (IL-10R1).
    reference_section_type: ABSTRACT
- id: PMID:12513909
  title: Comparison of interleukin-22 and interleukin-10 soluble receptor 
    complexes.
  findings:
  - statement: Compares IL-22 and IL-10 receptor complex formation.
    supporting_text: IL-22 and IL-10 require different ligand-specific receptor 
      chains (IL-22R and IL-10R1) but share a second receptor chain (IL-10R2) to
      initiate cellular responses.
    reference_section_type: ABSTRACT
- id: PMID:15837194
  title: Same structure, different function crystal structure of the 
    Epstein-Barr virus IL-10 bound to the soluble IL-10R1 chain.
  findings:
  - statement: Crystal structure of EBV IL-10 bound to IL-10R1, informing human 
      IL-10/receptor interaction.
    supporting_text: These functional differences have been correlated with the 
      approximately 1000-fold lower affinity of vIL-10, compared to hIL-10, for 
      the IL-10R1 receptor chain.
    reference_section_type: ABSTRACT
- id: PMID:20462497
  title: Structure and mechanism of receptor sharing by the IL-10R2 common 
    chain.
  findings:
  - statement: Structural basis for IL-10R2 (IL-10RB) sharing among IL-10 family
      cytokines.
    supporting_text: IL-10R2 is a shared cell surface receptor required for the 
      activation of five class 2 cytokines (IL-10, IL-22, IL-26, IL-28, and 
      IL-29) that play critical roles in host defense.
    reference_section_type: ABSTRACT
- id: PMID:35443184
  title: Human IL-10-producing B cells have diverse states that are induced from
    multiple B cell subsets.
  findings:
  - statement: Characterizes diverse IL-10-producing B cell populations.
    supporting_text: Regulatory B cells (Bregs) suppress immune responses 
      through the secretion of interleukin-10 (IL-10).
    reference_section_type: ABSTRACT
- id: PMID:24994464
  title: Low IL10 serum levels as key factor for predicting the sustained 
    virological response to IFNα/ribavirin in Brazilian patients with HCV 
    carrying IL28B CT/TT genotype.
  findings:
  - statement: Measures IL-10 serum levels in HCV patients, confirming IL-10 as 
      a circulating cytokine.
    supporting_text: the levels of IL10 seem to influence response to IFNα/RIB 
      therapy
    reference_section_type: ABSTRACT
- id: PMID:23071313
  title: IL-10-induced microRNA-187 negatively regulates TNF-α, IL-6, and 
    IL-12p40 production in TLR4-stimulated monocytes.
  findings:
  - statement: IL-10 induces miR-187 which suppresses pro-inflammatory cytokine 
      production.
    supporting_text: we identify miR-187 as an IL-10-dependent miRNA playing a 
      role in IL-10-mediated suppression of TNF-α, IL-6, and the p40 subunit of 
      IL-12
    reference_section_type: ABSTRACT
- id: PMID:16606666
  title: B7-H4 expression identifies a novel suppressive macrophage population 
    in human ovarian carcinoma.
  findings:
  - statement: IL-6 and IL-10 in the tumor microenvironment stimulate macrophage
      B7-H4 expression, contributing to immunosuppression.
    supporting_text: Interleukin (IL)-6 and IL-10 are found in high 
      concentrations in the tumor microenvironment. These cytokines stimulate 
      macrophage B7-H4 expression.
    reference_section_type: ABSTRACT
- id: PMID:17875732
  title: Relationship between B7-H4, regulatory T cells, and patient outcome in 
    human ovarian carcinoma.
  findings:
  - statement: Treg cells enable macrophages to produce IL-10 and IL-6, which in
      turn stimulate B7-H4 expression on macrophages in an autocrine manner.
    supporting_text: Tumor Treg cells enabled macrophages to spontaneously 
      produce interleukin (IL)-10 and IL-6. Tumor macrophages stimulated B7-H4 
      expression in an autocrine manner through IL-10 and IL-6.
    reference_section_type: ABSTRACT
- id: PMID:33737461
  title: Structure-based decoupling of the pro- and anti-inflammatory functions 
    of interleukin-10.
  findings:
  - statement: Decouples IL-10 pro- and anti-inflammatory functions through 
      structural analysis.
    supporting_text: IL-10 variants with a range of IL-10Rβ binding strengths 
      uncovered substantial differences in response thresholds across immune 
      cell populations, providing a means of manipulating IL-10 cell type 
      selectivity.
    reference_section_type: ABSTRACT
- id: PMID:31611251
  title: Biology and therapeutic potential of interleukin-10.
  findings:
  - statement: Comprehensive review of IL-10 biology and therapeutic 
      applications.
    supporting_text: The cytokine IL-10 is a key anti-inflammatory mediator 
      ensuring protection of a host from over-exuberant responses to pathogens 
      and microbiota, while playing important roles in other settings as sterile
      wound healing, autoimmunity, cancer, and homeostasis.
    reference_section_type: ABSTRACT
- id: PMID:21857966
  title: WNT5A signaling contributes to Aβ-induced neuroinflammation and 
    neurotoxicity.
  findings:
  - statement: IL-10 referenced as anti-inflammatory cytokine in 
      neuroinflammation context.
    supporting_text: activation of Wnt5a signaling elicited the expression of 
      proinflammatory cytokines IL-1β and TNF-α whereas inhibition of Wnt5a 
      signaling attenuated the Aβ-induced expression of the cytokines in 
      cortical cultures.
    reference_section_type: ABSTRACT
- id: PMID:21323571
  title: Pro/anti-inflammatory cytokines in the pathogenesis of premature 
    coronary artery disease.
  findings:
  - statement: IL-10 measured as anti-inflammatory cytokine in coronary artery 
      disease.
    supporting_text: Proinflammatory interleukin-18 (IL-18), high-sensitivity 
      C-reactive protein (hS-CRP), tumor necrosis factor-alpha (TNF-alpha), and 
      anti-inflammatory IL-10 are involved in the pathogenesis of 
      atherosclerosis.
    reference_section_type: ABSTRACT
- id: PMID:16034134
  title: IL-4 and IL-13 induce protection of porcine endothelial cells from 
    killing by human complement and from apoptosis through activation of a 
    phosphatidylinositide 3-kinase/Akt pathway.
  findings:
  - statement: IL-10 tested as negative control; does not protect endothelial 
      cells from complement or apoptosis.
    supporting_text: porcine EC incubated with IL-4 or IL-13, but not with IL-10
      or IL-11, became protected from killing by complement and apoptosis 
      induced by TNF-alpha plus cycloheximide.
    reference_section_type: ABSTRACT
- id: PMID:9847016
  title: Human interleukin 10 suppresses production of inflammatory mediators by
    LPS-stimulated equine peritoneal macrophages.
  findings:
  - statement: IL-10 suppresses inflammatory mediator production in 
      LPS-stimulated macrophages.
    supporting_text: Preincubation of LPS-stimulated peritoneal macrophages with
      rhuIL-10 caused significant (P<0.05) reduction in secretion of TNF, IL-6, 
      and PGE2, in a dose-dependent manner.
    reference_section_type: ABSTRACT
- id: PMID:18383040
  title: Interleukin-10 regulates TNF-alpha-converting enzyme (TACE/ADAM-17) 
    involving a TIMP-3 dependent and independent mechanism.
  findings:
  - statement: IL-10 regulates TACE/ADAM-17 ectodomain proteolysis activity.
    supporting_text: In the presence of IL-10, TNF-alpha production and 
      activation of surface TACE was significantly inhibited.
    reference_section_type: ABSTRACT
- id: PMID:17449476
  title: Eis (enhanced intracellular survival) protein of Mycobacterium 
    tuberculosis disturbs the cross regulation of T-cells.
  findings:
  - statement: IL-10 involved in T cell cross-regulation during M. tuberculosis 
      infection.
    supporting_text: Treatment of T-cells with Eis inhibits ERK1/2, JAK pathway,
      and subsequent production of tumor necrosis factor-alpha and 
      interleukin-4. On the contrary, there is increased production of 
      interferon-gamma and interleukin-10
    reference_section_type: ABSTRACT
- id: PMID:1371884
  title: Interleukin 10 is a potent growth and differentiation factor for 
    activated human B lymphocytes.
  findings:
  - statement: IL-10 identified as a potent growth and differentiation factor 
      for activated B cells.
    supporting_text: human and viral IL-10 stimulate DNA replication of B 
      lymphocytes activated either via their antigen receptor or via their CD40 
      antigen.
    reference_section_type: ABSTRACT
- id: PMID:22962438
  title: Complement receptor type 1 (CR1, CD35) is a potent inhibitor of B-cell 
    functions in rheumatoid arthritis patients.
  findings:
  - statement: IL-10 and IL-6 genetic interaction in B cell function and 
      immunoglobulin/plasma cell differentiation.
    supporting_text: Besides blocking B-cell receptor-induced proliferation, CR1
      inhibits the differentiation of B cells to plasmablasts and their 
      immunoglobulin production.
    reference_section_type: ABSTRACT
- id: file:human/IL10/IL10-deep-research-falcon.md
  title: Deep research synthesis of IL-10 literature
  findings: []
core_functions:
- description: IL-10 binds its receptor complex comprising IL-10RA 
    (ligand-binding) and IL-10RB (signal-transducing). This is the primary 
    molecular function through which IL-10 initiates all downstream signaling. 
    Supported by NAS (PMID:1847510), IEA, and structural studies 
    (PMID:16982608).
  molecular_function:
    id: GO:0005141
    label: interleukin-10 receptor binding
  directly_involved_in:
  - id: GO:0140105
    label: interleukin-10-mediated signaling pathway
  - id: GO:0046427
    label: positive regulation of receptor signaling pathway via JAK-STAT
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: PMID:1847510
    supporting_text: Seminal paper cloning human IL-10 cDNA and establishing 
      receptor binding.
    full_text_unavailable: true
  - reference_id: PMID:16982608
    supporting_text: Structural and signaling study of IL-10 receptor 
      interaction.
    full_text_unavailable: true
- description: IL-10 is the prototypical anti-inflammatory cytokine. Cytokine 
    activity is supported by IBA, IDA (PMID:24994464), NAS (PMID:10443688), and 
    IEA evidence.
  molecular_function:
    id: GO:0005125
    label: cytokine activity
  directly_involved_in:
  - id: GO:0050728
    label: negative regulation of inflammatory response
  - id: GO:0006955
    label: immune response
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: PMID:1940799
    supporting_text: IL-10, added to monocytes, strongly inhibited the 
      production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and 
      G-CSF at the transcriptional level.
    full_text_unavailable: true
  - reference_id: PMID:10443688
    supporting_text: Key primary study supporting IL-10 cytokine activity and 
      anti-inflammatory function.
    full_text_unavailable: true