Interleukin-4 (IL-4) is a secreted four-helix bundle cytokine of the IL-4/IL-13 family, produced primarily by Th2 cells, basophils, mast cells, eosinophils, and group 2 innate lymphoid cells (ILC2s). It functions as the master regulator of type 2 immunity by binding the IL-4 receptor alpha chain (IL4RA) and signaling through two receptor complexes: the type I complex (IL4RA/IL2RG) on hematopoietic cells, and the type II complex (IL4RA/IL13RA1) on non-hematopoietic and some hematopoietic cells. IL-4 signals canonically through JAK1/JAK3-STAT6, leading to GATA3 induction that drives Th2 differentiation, B cell class switch recombination to IgE and IgG4, MHC class II upregulation on B cells, and M2 macrophage polarization. IL-4 also activates IRS-2/PI3K pathways contributing to cell survival and proliferation. It is a central mediator of allergic inflammation, anti-helminth defense, and various immune regulatory processes. The protein has three disulfide bonds (Cys3-Cys127, Cys24-Cys65, Cys46-Cys99) and one N-glycosylation site (Asn62). An alternatively spliced isoform (IL-4delta2) lacking exon 2 acts as a natural antagonist.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0035771
interleukin-4-mediated signaling pathway
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: IL-4 is the defining ligand of the IL-4-mediated signaling pathway. It binds IL4RA to initiate JAK/STAT6 signaling cascades that drive Th2 differentiation, IgE class switching, and other downstream effects. This is a core biological process for IL-4.
Reason: This is the most specific and appropriate BP term for IL-4 as the initiating ligand of this pathway. The IBA annotation is phylogenetically well-supported and represents the central biological role of the protein. Extensively documented in the deep research and UniProt function annotation.
Supporting Evidence:
file:human/IL4/IL4-deep-research-falcon.md
IL-4 signals via two receptor complexes...type I (IL-4R-alpha/gamma-c) largely on hematopoietic cells and type II (IL-4R-alpha/IL-13R-alpha1) on many non-hematopoietic cells. JAK-STAT is canonical...converging on STAT6
PMID:12574355
IL-4-dependent AID induction was inhibited by a dominant-negative STAT6, indicating that IL-4 induced AID expression via the Janus kinase (JAK)/STAT6 signaling pathway
|
|
GO:0045893
positive regulation of DNA-templated transcription
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: IL-4 signaling via STAT6 activates transcription of numerous target genes including GATA3, germline Ig epsilon transcripts, CD23, and MHC class II genes. This is a well-established downstream consequence of IL-4 signaling.
Reason: IL-4 is well-documented as a transcriptional activator through STAT6-mediated signaling. The IBA annotation is broadly correct and represents a core downstream activity. This is a general term but appropriate for a cytokine with pleiotropic transcriptional effects.
Supporting Evidence:
PMID:12574355
IL-4 was able to induce AID expression in human primary B cells and B cell lines, and IL-4-induced AID expression was further enhanced by CD40 signaling
PMID:20554961
IL-4 promotes Th2 development by inducing the expression of the GATA3 transcription factor
|
|
GO:0050776
regulation of immune response
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: IL-4 is a major immunoregulatory cytokine that shapes adaptive immune responses by driving Th2 polarization, B cell activation and class switching, and M2 macrophage polarization, while simultaneously suppressing Th1 responses.
Reason: This is a broad but accurate term for IL-4. As a key immunoregulatory cytokine, IL-4 fundamentally regulates immune responses. The IBA annotation is well-supported. While more specific terms exist and are also annotated, this general term appropriately captures the broad immunoregulatory role.
Supporting Evidence:
file:human/IL4/IL4-deep-research-falcon.md
IL-4 is a central driver of type-2 endotypes (eosinophilic/allergic) across airway and barrier diseases
|
|
GO:0050728
negative regulation of inflammatory response
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: IL-4 has well-documented anti-inflammatory properties, particularly in suppressing pro-inflammatory Th1/M1 macrophage responses, inhibiting TNF-alpha production, and promoting M2 (anti-inflammatory) macrophage polarization. This is a core function of IL-4 in immune regulation.
Reason: IL-4 is a canonical anti-inflammatory cytokine that promotes M2 macrophage polarization and suppresses pro-inflammatory cytokine production. The IBA annotation is phylogenetically well-supported and consistent with extensive experimental evidence.
Supporting Evidence:
file:human/IL4/IL4-deep-research-falcon.md
IL-4 drives...alternative (M2) macrophage activation
|
|
GO:0005125
cytokine activity
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: IL-4 is by definition a cytokine - a secreted signaling molecule that modulates immune cell behavior. This is the most fundamental molecular function classification for IL-4.
Reason: IL-4 is unambiguously a cytokine. The IEA annotation from UniProt keyword mapping is correct and consistent with the IDA annotation for the same term. This broad MF term is appropriate alongside the more specific GO:0005136 (interleukin-4 receptor binding).
Supporting Evidence:
file:human/IL4/IL4-uniprot.txt
Cytokine secreted primarily by mast cells, T-cells, eosinophils, and basophils that plays a role in regulating antibody production, hematopoiesis and inflammation
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GO:0005126
cytokine receptor binding
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: IL-4 binds cytokine receptors (IL4RA, IL13RA1) as part of its signaling mechanism. This is a parent term of the more specific GO:0005136 (interleukin-4 receptor binding).
Reason: This is a correct but less specific parent term. Since the more specific GO:0005136 is also annotated, this IEA annotation is redundant but not incorrect. Acceptable as an IEA capturing the broader category.
Supporting Evidence:
file:human/IL4/IL4-uniprot.txt
Upon binding to IL4, IL4R receptor dimerizes either with the common IL2R gamma chain/IL2RG...or with the IL13RA1
|
|
GO:0005136
interleukin-4 receptor binding
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: IL-4 specifically binds the IL-4 receptor alpha chain (IL4RA) at its site I interface (helices A-C, key residues Glu9/Arg88). This is the most specific and informative MF term for IL-4.
Reason: This is the core molecular function of IL-4 as a ligand. The IEA annotation from InterPro domain mapping is correct and supported by extensive structural and biochemical data, including crystal structures of the IL-4/IL4RA complex.
Supporting Evidence:
file:human/IL4/IL4-uniprot.txt
Interacts with IL4R...Interacts with IL13RA1
file:human/IL4/IL4-deep-research-falcon.md
structure-function mapping identifies site I on helices A-C as the IL-4R-alpha interface (key residues Glu9, Arg88)
|
|
GO:0005576
extracellular region
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: IL-4 is a secreted cytokine that functions in the extracellular region. UniProt annotates it as Secreted.
Reason: IL-4 is a secreted protein with a signal peptide (residues 1-24). The extracellular region localization is correct and well-established. This is broader than GO:0005615 (extracellular space) but acceptable as an IEA annotation.
Supporting Evidence:
file:human/IL4/IL4-uniprot.txt
SUBCELLULAR LOCATION: Secreted
|
|
GO:0005615
extracellular space
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: IL-4 is secreted into the extracellular space where it functions as a paracrine/ autocrine signaling molecule.
Reason: Correct IEA annotation consistent with the IDA evidence for the same term. IL-4 is a secreted cytokine that acts in the extracellular space.
Supporting Evidence:
file:human/IL4/IL4-uniprot.txt
SUBCELLULAR LOCATION: Secreted
|
|
GO:0006955
immune response
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: IL-4 is a key mediator of immune responses, particularly type 2 immunity. This is a very broad BP term.
Reason: This is a very general but correct IEA annotation. IL-4 is fundamentally an immune response mediator. More specific terms are also annotated. Acceptable as a broad IEA classification.
Supporting Evidence:
file:human/IL4/IL4-uniprot.txt
Cytokine secreted primarily by mast cells, T-cells, eosinophils, and basophils that plays a role in regulating antibody production, hematopoiesis and inflammation, and the development of effector T-cell responses
|
|
GO:0008083
growth factor activity
|
IEA
GO_REF:0000120 |
KEEP AS NON CORE |
Summary: IL-4 was historically known as B-cell stimulatory factor 1 (BSF-1) and promotes proliferation of B and T cells. However, its primary identity is as a cytokine rather than a classical growth factor.
Reason: While IL-4 does promote cell proliferation (B cells, T cells), its primary molecular function is better described as cytokine activity (GO:0005125) and IL-4 receptor binding (GO:0005136). Growth factor activity is a secondary characterization. The UniProt keyword mapping that generated this annotation reflects the historical BSF-1 naming but is not the most informative descriptor.
Supporting Evidence:
file:human/IL4/IL4-uniprot.txt
AltName...B-cell stimulatory factor 1; Short=BSF-1
|
|
GO:0010628
positive regulation of gene expression
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: IL-4 upregulates expression of numerous genes through STAT6 signaling, including GATA3, AID, germline Ig epsilon transcripts, CD23, and MHC class II molecules.
Reason: This is a broad but correct IEA annotation from ARBA. IL-4 is a potent inducer of gene expression in immune cells. More specific transcription regulation terms are also annotated.
Supporting Evidence:
PMID:12574355
IL-4 was able to induce AID expression in human primary B cells and B cell lines
|
|
GO:0030335
positive regulation of cell migration
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: IL-4 can promote cell migration in certain contexts, including macrophage and tumor cell migration. This is a secondary, context-dependent effect.
Reason: While there is evidence that IL-4 can regulate cell migration, this is not a core function of the cytokine. It represents a pleiotropic downstream effect rather than the primary evolved function. The ARBA-generated IEA annotation is acceptable but should not be considered a defining function.
|
|
GO:0042113
B cell activation
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: IL-4 is a major B cell activating factor that induces B cell proliferation, class switching to IgE and IgG, and upregulation of MHC class II and CD23. This is one of the historically defining functions of IL-4 (originally named B-cell stimulatory factor 1).
Reason: B cell activation is a core function of IL-4. The IEA from UniProt keyword mapping accurately reflects that IL-4 was originally identified as BSF-1 precisely because of its B cell activating properties.
Supporting Evidence:
file:human/IL4/IL4-uniprot.txt
Induces the expression of class II MHC molecules on resting B-cells. Enhances both secretion and cell surface expression of IgE and IgG1
|
|
GO:0045321
leukocyte activation
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: IL-4 activates multiple leukocyte types including B cells, T cells, macrophages, and dendritic cells. This is a broad parent term.
Reason: This broad IEA term is correct. IL-4 activates multiple leukocyte populations. More specific child terms (B cell activation, T cell activation, macrophage activation) are also annotated.
|
|
GO:0051239
regulation of multicellular organismal process
|
IEA
GO_REF:0000117 |
MARK AS OVER ANNOTATED |
Summary: IL-4 regulates immune processes at the organismal level, affecting allergic responses, anti-helminth immunity, and tissue remodeling.
Reason: This is an extremely broad and uninformative term. While technically true, it provides no useful information about IL-4 function. More specific terms are available and annotated. The ARBA machine learning annotation is too general to be informative.
|
|
GO:0080090
regulation of primary metabolic process
|
IEA
GO_REF:0000117 |
MARK AS OVER ANNOTATED |
Summary: IL-4 can regulate metabolic processes in target cells, but this is an extremely broad and uninformative annotation.
Reason: This term is far too general to be informative for IL-4 annotation. While IL-4 signaling does affect metabolic processes in target cells, this ARBA-generated term does not convey any meaningful biological insight about the protein.
|
|
GO:0005515
protein binding
|
IPI
PMID:10219247 Crystal structure of the interleukin-4/receptor alpha chain ... |
MODIFY |
Summary: PMID:10219247 reports the crystal structure of IL-4 in complex with IL4RA at 2.30 angstroms resolution, demonstrating direct protein-protein interaction. The WITH column specifies UniProtKB:P24394 (IL4R).
Reason: The protein binding annotation is uninformative. The interaction demonstrated in PMID:10219247 is specifically IL-4 binding to the IL-4 receptor alpha chain, which is better captured by GO:0005136 (interleukin-4 receptor binding), which is already annotated via IEA, TAS, and IDA evidence.
Proposed replacements:
interleukin-4 receptor binding
Supporting Evidence:
PMID:10219247
IL-4 binds with high affinity and specificity to the ectodomain of the IL-4 receptor alpha chain (IL4-BP)
file:human/IL4/IL4-uniprot.txt
X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 25-153 IN COMPLEX WITH IL4R...INTERACTION WITH IL4R
|
|
GO:0005515
protein binding
|
IPI
PMID:18243101 Molecular and structural basis of cytokine receptor pleiotro... |
MODIFY |
Summary: PMID:18243101 reports the crystal structure of IL-4 in complex with IL13RA1 and IL4RA, elucidating the molecular basis of cytokine receptor pleiotropy in the IL-4/IL-13 system. The GOA TSV shows two separate annotations from this PMID, one with IL4R (P24394) and one with IL13RA1 (P78552).
Reason: The generic protein binding term is uninformative. The interaction with IL4RA is better captured by GO:0005136, and the interaction with IL13RA1 represents a component of the type II receptor complex formation.
Proposed replacements:
interleukin-4 receptor binding
Supporting Evidence:
PMID:18243101
Here we present the crystal structures of the complete set of type I (IL-4R alpha/gamma(c)/IL-4) and type II (IL-4R alpha/IL-13R alpha1/IL-4, IL-4R alpha/IL-13R alpha1/IL-13) ternary signaling complexes
file:human/IL4/IL4-uniprot.txt
X-RAY CRYSTALLOGRAPHY (2.93 ANGSTROMS) OF 25-153...INTERACTION WITH IL13RA1, AND FUNCTION
|
|
GO:0005515
protein binding
|
IPI
PMID:23597562 Inhibition of tumor angiogenesis and growth by a small-molec... |
MODIFY |
Summary: PMID:23597562 is about a small-molecule FGFR inhibitor (SSR128129E) and its anti-tumor angiogenesis effects. The WITH column specifies IL4R (P24394). This annotation likely derives from an IntAct high-throughput dataset associated with this publication where IL4-IL4R interaction was detected.
Reason: The IL-4/IL-4R interaction is well-established but the generic protein binding term is uninformative. If the interaction is genuine, it is better captured by GO:0005136 (interleukin-4 receptor binding). Additionally, the primary publication focus is FGFR biology, making the provenance of this specific annotation unclear.
Proposed replacements:
interleukin-4 receptor binding
Supporting Evidence:
PMID:23597562
we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling
|
|
GO:0005515
protein binding
|
IPI
PMID:8266078 Interleukin-2 receptor gamma chain: a functional component o... |
MODIFY |
Summary: PMID:8266078 demonstrates that the IL-2 receptor gamma chain is a functional component of the IL-4 receptor, showing IL-4 binding and signaling through the IL4RA/IL2RG complex.
Reason: As with the other protein binding annotations for IL-4, the interaction with IL4R is better captured by the specific term GO:0005136 (interleukin-4 receptor binding). The generic protein binding term is uninformative.
Proposed replacements:
interleukin-4 receptor binding
Supporting Evidence:
PMID:8266078
IL-2R gamma was demonstrated to be a component of the IL-4 receptor on the basis of chemical cross-linking data, the ability of IL-2R gamma to augment IL-4 binding affinity, and the requirement for IL-2R gamma in IL-4-mediated phosphorylation of insulin receptor substrate-1
|
|
GO:0007259
cell surface receptor signaling pathway via JAK-STAT
|
IDA
PMID:23103943 Redirecting cell-type specific cytokine responses with engin... |
ACCEPT |
Summary: IL-4 signals through JAK1/JAK3 (type I receptor) and JAK1/TYK2 (type II receptor) to activate STAT6, and to a lesser extent STAT3. This annotation captures the canonical signaling mechanism.
Reason: JAK-STAT signaling is the primary intracellular signaling pathway activated by IL-4. The IDA annotation from ComplexPortal is well-supported by extensive literature.
Supporting Evidence:
PMID:23103943
Formation of the IL-4/IL-4Rα/γc or IL-4/IL-4Rα/IL-13Rα1 complex on the cell surface activates intracellular signaling pathways including the Jak-STAT and the PI3K/Akt pathways
file:human/IL4/IL4-uniprot.txt
Engagement of both types of receptors initiates JAK3 and to a lower extend JAK1 phosphorylation leading to activation of the signal transducer and activator of transcription 6/STAT6
file:human/IL4/IL4-deep-research-falcon.md
JAK-STAT is canonical...type I (primarily JAK1/JAK3) and type II (JAK2/TYK2 reported), converging on STAT6
|
|
GO:0035771
interleukin-4-mediated signaling pathway
|
NAS
PMID:18243101 Molecular and structural basis of cytokine receptor pleiotro... |
ACCEPT |
Summary: PMID:18243101 elucidated the structural basis for cytokine receptor pleiotropy in the IL-4/IL-13 system, providing mechanistic insight into IL-4 signaling through both type I and type II receptor complexes.
Reason: This NAS annotation is well-supported. The referenced paper provides definitive structural evidence for IL-4 receptor complex assembly, which is the initiating event of the IL-4-mediated signaling pathway. Duplicate of the IBA annotation but with different evidence, which is acceptable.
Supporting Evidence:
PMID:18243101
Here we present the crystal structures of the complete set of type I (IL-4R alpha/gamma(c)/IL-4) and type II (IL-4R alpha/IL-13R alpha1/IL-4, IL-4R alpha/IL-13R alpha1/IL-13) ternary signaling complexes
file:human/IL4/IL4-uniprot.txt
X-RAY CRYSTALLOGRAPHY...OF 25-153, DISULFIDE BONDS, INTERACTION WITH IL13RA1, AND FUNCTION
|
|
GO:0042531
positive regulation of tyrosine phosphorylation of STAT protein
|
NAS
PMID:18243101 Molecular and structural basis of cytokine receptor pleiotro... |
ACCEPT |
Summary: IL-4 receptor engagement leads to JAK-mediated phosphorylation of STAT6 (at Y641) and STAT3 (at Y705). This is a direct mechanistic consequence of IL-4 signaling.
Reason: STAT6 tyrosine phosphorylation is the key signaling event downstream of IL-4 receptor activation. The NAS annotation from ComplexPortal accurately captures this core signaling mechanism. The Reactome pathway also documents JAK1 phosphorylation of STAT3 and STAT6.
Supporting Evidence:
file:human/IL4/IL4-uniprot.txt
Engagement of both types of receptors initiates JAK3 and to a lower extend JAK1 phosphorylation leading to activation of the signal transducer and activator of transcription 6/STAT6
PMID:12574355
IL-4-dependent AID induction was inhibited by a dominant-negative STAT6, indicating that IL-4 induced AID expression via the Janus kinase (JAK)/STAT6 signaling pathway
|
|
GO:1902107
positive regulation of leukocyte differentiation
|
NAS
PMID:23103943 Redirecting cell-type specific cytokine responses with engin... |
ACCEPT |
Summary: IL-4 drives differentiation of multiple leukocyte lineages including Th2 cells from naive T cells, dendritic cells from monocytes, and M2 macrophages from monocytes/ macrophages.
Reason: This is a well-supported annotation. IL-4 is a key driver of leukocyte differentiation programs, particularly Th2 differentiation and dendritic cell differentiation. The NAS evidence from ComplexPortal is consistent with extensive experimental data.
Supporting Evidence:
PMID:23103943
Cytokines dimerize their receptors, with the binding of the 'second chain' triggering signaling
file:human/IL4/IL4-deep-research-falcon.md
IL-4 drives Th2 differentiation (via STAT6->GATA3), B-cell proliferation and class-switch recombination to IgE, and alternative (M2) macrophage activation
|
|
GO:0007259
cell surface receptor signaling pathway via JAK-STAT
|
IGI
PMID:12574355 Human activation-induced cytidine deaminase is induced by IL... |
ACCEPT |
Summary: PMID:12574355 demonstrates that IL-4 induces AID expression via JAK/STAT6 signaling, and that CD45 negatively regulates this pathway by acting as a JAK phosphatase. The IGI annotation with STAT6 (P42226) provides genetic interaction evidence.
Reason: The paper directly demonstrates IL-4 activates JAK/STAT6 signaling using dominant- negative STAT6 experiments. The genetic interaction with STAT6 provides strong evidence for this pathway annotation.
Supporting Evidence:
PMID:12574355
IL-4-dependent AID induction was inhibited by a dominant-negative STAT6, indicating that IL-4 induced AID expression via the Janus kinase (JAK)/STAT6 signaling pathway
|
|
GO:0035771
interleukin-4-mediated signaling pathway
|
IDA
PMID:12574355 Human activation-induced cytidine deaminase is induced by IL... |
ACCEPT |
Summary: PMID:12574355 directly demonstrates IL-4 signaling through JAK/STAT6 in the context of AID gene induction in B cells.
Reason: The paper provides direct experimental evidence for IL-4-mediated signaling pathway activation using IL-4 stimulation of B cells and demonstrating JAK-dependent STAT6 activation.
Supporting Evidence:
PMID:12574355
IL-4 was able to induce AID expression in human primary B cells and B cell lines...IL-4-induced AID expression was further enhanced by CD40 signaling
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IGI
PMID:12574355 Human activation-induced cytidine deaminase is induced by IL... |
ACCEPT |
Summary: PMID:12574355 shows IL-4 induces AID gene transcription through STAT6-dependent mechanisms. The IGI evidence includes interactions with CD45 (P08575), CD40 (P29965), and STAT6 (P42226).
Reason: The paper demonstrates IL-4 positively regulates transcription of the AID gene in B cells, with genetic interaction evidence from STAT6 dominant-negative, CD45, and CD40 experiments.
Supporting Evidence:
PMID:12574355
IL-4 was able to induce AID expression in human primary B cells and B cell lines, and IL-4-induced AID expression was further enhanced by CD40 signaling
|
|
GO:0005125
cytokine activity
|
IDA
PMID:10219247 Crystal structure of the interleukin-4/receptor alpha chain ... |
ACCEPT |
Summary: PMID:10219247 reports the crystal structure of the IL-4/IL4RA complex and characterizes the receptor binding interface, providing direct structural evidence for IL-4's cytokine activity.
Reason: This IDA annotation is well-supported. The referenced paper demonstrates direct IL-4/receptor interaction through structural analysis, confirming IL-4 functions as a cytokine that binds and activates its cognate receptor.
Supporting Evidence:
PMID:10219247
Interleukin-4 (IL-4) is a principal regulatory cytokine during an immune response and a crucial determinant for allergy and asthma
file:human/IL4/IL4-uniprot.txt
Crystal structure of the interleukin-4/receptor alpha chain complex reveals a mosaic binding interface
|
|
GO:0005615
extracellular space
|
IDA
PMID:3279117 Modulation of phenotypic and functional properties of human ... |
ACCEPT |
Summary: PMID:3279117 demonstrates that exogenous recombinant IL-4 acts on monocytes in culture, confirming its activity as a secreted extracellular protein. The paper shows IL-4 modulates monocyte phenotype and function when added to culture medium.
Reason: IL-4 is a secreted cytokine with a signal peptide. Its localization to the extracellular space is unambiguous. The paper demonstrates IL-4 acting as an extracellular factor on monocytes.
Supporting Evidence:
PMID:3279117
Highly purified peripheral blood monocytes were cultured in the presence of rIL-4
file:human/IL4/IL4-uniprot.txt
SUBCELLULAR LOCATION: Secreted
|
|
GO:0035771
interleukin-4-mediated signaling pathway
|
IDA
PMID:10219247 Crystal structure of the interleukin-4/receptor alpha chain ... |
ACCEPT |
Summary: PMID:10219247 provides structural evidence for IL-4 receptor complex formation, the initiating event of the IL-4-mediated signaling pathway.
Reason: The crystal structure of IL-4 bound to IL4RA demonstrates the molecular basis of IL-4 signaling initiation. This IDA annotation is well-supported and consistent with other annotations for the same GO term.
Supporting Evidence:
PMID:10219247
this intermediate complex recruits the common gamma chain (gamma c), thereby initiating transmembrane signaling
file:human/IL4/IL4-uniprot.txt
Crystal structure of the interleukin-4/receptor alpha chain complex reveals a mosaic binding interface
|
|
GO:0000122
negative regulation of transcription by RNA polymerase II
|
IDA
PMID:11967989 Interleukin-4 regulates connective tissue growth factor expr... |
KEEP AS NON CORE |
Summary: PMID:11967989 shows that IL-4 attenuates TGF-beta-stimulated induction of CTGF mRNA expression in human lung fibroblasts, through interference with TGF-beta-induced transcriptional activation of the CTGF gene.
Reason: The paper demonstrates IL-4 can negatively regulate specific gene transcription (CTGF), but this is a context-specific effect in lung fibroblasts rather than a core function of IL-4. IL-4's primary role is transcriptional activation of immune genes, not transcriptional repression.
Supporting Evidence:
PMID:11967989
IL-4 attenuated the TGF-beta-stimulated induction of CTGF mRNA expression by 50%...IL-4 interfered with the TGF-beta-induced transcriptional activation of the CTGF gene
|
|
GO:1903845
negative regulation of cellular response to transforming growth factor beta stimulus
|
IDA
PMID:11967989 Interleukin-4 regulates connective tissue growth factor expr... |
KEEP AS NON CORE |
Summary: PMID:11967989 directly demonstrates that IL-4 antagonizes TGF-beta signaling in lung fibroblasts by attenuating TGF-beta-induced CTGF expression.
Reason: While the paper provides direct evidence for this annotation, IL-4's antagonism of TGF-beta signaling in fibroblasts is a tissue-specific context-dependent effect, not a core function of the cytokine. This represents pleiotropic activity.
Supporting Evidence:
PMID:11967989
IL-4 attenuated the TGF-beta-stimulated induction of CTGF mRNA expression by 50%. This effect was selective because IL-4 did not affect fibronectin or alpha1(I) collagen mRNA expression induced by TGF-beta
|
|
GO:0008284
positive regulation of cell population proliferation
|
IGI
PMID:31432141 miR‑320a upregulation contributes to the development of pree... |
KEEP AS NON CORE |
Summary: PMID:31432141 identifies IL-4 as a direct target of miR-320a in trophoblast cells (HTR-8/SVneo). Rescue experiments demonstrate that IL-4 overexpression partially reverses the anti-proliferative effect of miR-320a on trophoblast cells (MTT assay). The IGI evidence involves miR-320a (RNAcentral:URS00003CF1AD_9606) with acts_upstream_of_or_within qualifier. The proliferation effect is in trophoblast cells in the context of preeclampsia.
Reason: The paper provides evidence that IL-4 promotes trophoblast cell proliferation in the preeclampsia context. While IL-4 also promotes B and T cell proliferation as a core function (annotated separately via ISS), this specific annotation reflects a non-immune cell proliferation effect that is not a core function of the cytokine.
Supporting Evidence:
PMID:31432141
restoring the expression level of IL-4 partially decreased the inhibitory effect of miR-320a overexpression on HTR-8/SVneo cell proliferation
PMID:31432141
Collectively, the present data suggested that IL-4 was a functional target gene of miR-320a, and miR-320a upregulation inhibited the proliferation and invasion of HTR-8/SVneo cells by directly targeting IL-4
|
|
GO:0030335
positive regulation of cell migration
|
IGI
PMID:31432141 miR‑320a upregulation contributes to the development of pree... |
KEEP AS NON CORE |
Summary: PMID:31432141 studies miR-320a in preeclampsia trophoblast cells (HTR-8/SVneo). IL-4 is identified as a direct target of miR-320a. Rescue experiments show that overexpression of IL-4 partially reverses the inhibitory effect of miR-320a on trophoblast cell invasion (Transwell assay). The IGI evidence involves miR-320a (RNAcentral:URS00003CF1AD_9606) as the interacting partner, with acts_upstream_of_or_within qualifier. The cell migration/invasion effect is in trophoblast cells, not immune cells.
Reason: The paper provides evidence that IL-4 promotes trophoblast cell invasion in the context of preeclampsia, which is consistent with the IEA annotation for the same term that was already marked KEEP_AS_NON_CORE. Cell migration promotion is not a core immune function of IL-4 but represents a pleiotropic effect in non-immune cell types.
Supporting Evidence:
PMID:31432141
overexpression of IL-4 in HTR-8/SVneo cells reduced the inhibitory effect of miR-320a overexpression on cell invasion
PMID:31432141
miR-320a upregulation inhibited the proliferation and invasion of HTR-8/SVneo cells by directly targeting IL-4
|
|
GO:0032733
positive regulation of interleukin-10 production
|
IGI
PMID:30634164 IL-16 regulates macrophage polarization as a target gene of ... |
ACCEPT |
Summary: PMID:30634164 studies macrophage polarization and shows that M2 macrophages (induced by IL-4 and IL-13) express higher levels of IL-10 than M1 macrophages. The IGI evidence involves IL-13 (P35225), reflecting the cooperative use of IL-4 and IL-13 in M2 polarization protocols.
Reason: The paper demonstrates that IL-4/IL-13-induced M2 macrophages express higher IL-10 levels than M1 macrophages, supporting IL-4's role in promoting IL-10 production. This is consistent with IL-4's well-established anti-inflammatory M2-polarizing function and the known IL-10 production by M2 macrophages.
Supporting Evidence:
PMID:30634164
M1 macrophages express higher levels of IL-16 than M2 macrophages but express lower levels of IL-10 and mir-145 than M2 cells
|
|
GO:0042116
macrophage activation
|
IGI
PMID:30634164 IL-16 regulates macrophage polarization as a target gene of ... |
ACCEPT |
Summary: PMID:30634164 uses IL-4 and IL-13 to induce M2 macrophage polarization from THP-1 monocytes. IL-4 is a canonical driver of alternative macrophage activation (M2 polarization). The IGI evidence with IL-13 (P35225) reflects the cooperative use of these cytokines in M2 polarization.
Reason: M2 macrophage activation by IL-4 is one of its best-established functions. The paper directly uses IL-4 in the M2 polarization protocol. This is extensively documented in the deep research and is a core function of IL-4 in innate immunity.
Supporting Evidence:
PMID:30634164
THP-1 cells were induced by IL-4 and IL-13 following PMA incubation (M2 polarized macrophages) or induced by IFN-gamma and LPS (M1 classical macrophage activation)
file:human/IL4/IL4-deep-research-falcon.md
IL-4 drives...alternative (M2) macrophage activation; IL-13 overlaps but acts more directly on structural cells
|
|
GO:0050728
negative regulation of inflammatory response
|
IGI
PMID:30634164 IL-16 regulates macrophage polarization as a target gene of ... |
ACCEPT |
Summary: PMID:30634164 demonstrates that IL-4/IL-13-induced M2 macrophages have an anti-inflammatory profile with high IL-10 and low pro-inflammatory cytokines. IL-4 suppresses inflammatory responses through M2 macrophage polarization. The IGI evidence with IL-13 (P35225) reflects cooperative anti-inflammatory signaling.
Reason: This is a duplicate of the IBA annotation for the same term, with independent IGI evidence. The anti-inflammatory role of IL-4 is well-established and represents a core function. Duplicate annotations with different evidence codes are acceptable.
Supporting Evidence:
PMID:30634164
THP-1 cells were induced by IL-4 and IL-13 following PMA incubation (M2 polarized macrophages) or induced by IFN-gamma and LPS (M1 classical macrophage activation)
file:human/IL4/IL4-deep-research-falcon.md
IL-4 drives...alternative (M2) macrophage activation
|
|
GO:0010628
positive regulation of gene expression
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: IL-4 upregulates gene expression in target cells through STAT6-mediated transcriptional activation. Transferred from mouse IL-4 (P07750) and rat IL-4 (P20096).
Reason: This ISS annotation is well-supported by the conserved function of IL-4 across mammals. IL-4 is a potent inducer of gene expression through STAT6 signaling. The annotation is consistent with the IDA evidence for transcription regulation and with the IEA annotation for the same term.
Supporting Evidence:
PMID:12574355
IL-4 was able to induce AID expression in human primary B cells and B cell lines
|
|
GO:0150076
neuroinflammatory response
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: IL-4 has been implicated in neuroinflammation, particularly in the context of neuroprotection and microglial polarization. Transferred from mouse IL-4 (P20096) by ARUK-UCL curators.
Reason: While IL-4 has documented roles in neuroinflammation (primarily anti-inflammatory/ neuroprotective effects via M2 microglial polarization), this is a tissue-specific context-dependent activity, not a core immune function of IL-4. The ISS from mouse is reasonable but this represents a specialized function.
|
|
GO:0032720
negative regulation of tumor necrosis factor production
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: IL-4 suppresses TNF-alpha production, particularly in macrophages, as part of its anti-inflammatory and M2-polarizing activity. Transferred from mouse IL-4 (P07750).
Reason: Suppression of TNF-alpha production is a well-established function of IL-4 in the context of its anti-inflammatory M2 macrophage polarization program. The ISS from mouse is appropriate given conserved IL-4 function.
Supporting Evidence:
file:human/IL4/IL4-deep-research-falcon.md
IL-4 drives...alternative (M2) macrophage activation
|
|
GO:1901857
positive regulation of cellular respiration
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: IL-4 has been reported to promote mitochondrial respiration in macrophages as part of M2 metabolic reprogramming. Transferred from mouse IL-4 (P07750) by ARUK-UCL.
Reason: While IL-4-driven M2 macrophage polarization involves metabolic reprogramming toward oxidative phosphorylation, this metabolic effect is a downstream consequence of M2 polarization rather than a core function of IL-4 itself. The annotation is not incorrect but represents a specialized downstream effect.
|
|
GO:2001171
positive regulation of ATP biosynthetic process
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Related to the metabolic reprogramming of M2 macrophages toward oxidative phosphorylation. Transferred from mouse IL-4 (P07750) by ARUK-UCL.
Reason: This is a highly specific metabolic effect that is downstream of M2 macrophage polarization. Not a core function of IL-4 as a cytokine. Over-specific annotation of a downstream metabolic consequence.
|
|
GO:0150079
negative regulation of neuroinflammatory response
|
IC
GO_REF:0000111 |
KEEP AS NON CORE |
Summary: IC annotation inferred from ISS evidence. IL-4 has anti-inflammatory effects in the CNS, promoting M2 microglial polarization and suppressing neuroinflammation.
Reason: While IL-4 has documented neuroprotective and anti-neuroinflammatory effects, these are tissue-specific activities rather than core immune functions. The IC evidence based on ISS is reasonable but this represents a specialized function.
|
|
GO:0048260
positive regulation of receptor-mediated endocytosis
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: IL-4 may promote receptor-mediated endocytosis in certain cell types, possibly related to amyloid-beta clearance by microglia. Transferred from mouse IL-4 (P07750 and P20096) by ARUK-UCL.
Reason: This annotation likely relates to IL-4's role in promoting microglial phagocytic clearance of amyloid-beta, which is a very specialized neuroimmune function rather than a core IL-4 activity.
|
|
GO:1900223
positive regulation of amyloid-beta clearance
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: IL-4 has been reported to promote amyloid-beta clearance by microglia in Alzheimer's disease models. Transferred from mouse IL-4 (P07750 and P20096) by ARUK-UCL.
Reason: While there is mouse literature supporting IL-4's role in promoting amyloid-beta clearance, this is a highly specialized neuroimmune function that is far from the core evolved function of IL-4 as an immune cytokine. The ISS transfer is reasonable but this represents a tissue-specific activity.
|
|
GO:0016239
positive regulation of macroautophagy
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: IL-4 has been reported to stimulate autophagy in dendritic cells. The UniProt function annotation notes IL-4 stimulates autophagy by interfering with mTORC1 signaling and through RUFY4 induction. Transferred from mouse IL-4 (P07750).
Reason: While UniProt documents this function, autophagy induction is a specialized downstream effect of IL-4 signaling rather than a core function. The ISS annotation is supported by the UniProt function description.
Supporting Evidence:
file:human/IL4/IL4-uniprot.txt
Stimulates autophagy in dendritic cells by interfering with mTORC1 signaling and through the induction of RUFY4
|
|
GO:0120162
positive regulation of cold-induced thermogenesis
|
ISS
PMID:24906148 Eosinophils and type 2 cytokine signaling in macrophages orc... |
KEEP AS NON CORE |
Summary: PMID:24906148 demonstrates that IL-4/IL-13 signaling in macrophages is required for cold-induced beige fat biogenesis. Administration of IL-4 to thermoneutral mice increases beige fat mass and thermogenic capacity. The ISS is from mouse IL-4 (P07750).
Reason: While the paper provides compelling evidence that IL-4 promotes beige fat thermogenesis through alternatively activated macrophages, this is a specialized metabolic function far removed from IL-4's core immune role.
Supporting Evidence:
PMID:24906148
Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced biogenesis of beige fat
PMID:24906148
administration of IL-4 to thermoneutral mice increases beige fat mass and thermogenic capacity to ameliorate pre-established obesity
|
|
GO:0042110
T cell activation
|
IGI
PMID:18337562 CCL5-mediated T-cell chemotaxis involves the initiation of m... |
UNDECIDED |
Summary: PMID:18337562 is about CCL5-mediated T cell chemotaxis involving mTOR/4E-BP1 translation initiation. The paper studied CD4+ T cell migration in response to CCL5, not IL-4. The IGI evidence involves CD82 (P10747). The connection to IL-4 is unclear.
Reason: The referenced publication (PMID:18337562) is about CCL5 (RANTES)-mediated T cell chemotaxis, not IL-4 function. While IL-4 is known to activate T cells (particularly driving Th2 differentiation), this specific annotation appears to reference an unrelated paper. The annotation may have been made based on a secondary finding or data in the paper, but the primary focus is CCL5.
Supporting Evidence:
PMID:18337562
CCL5-mediated T-cell chemotaxis involves the initiation of mRNA translation through mTOR/4E-BP1
|
|
GO:0045892
negative regulation of DNA-templated transcription
|
IDA
PMID:16606666 B7-H4 expression identifies a novel suppressive macrophage p... |
KEEP AS NON CORE |
Summary: PMID:16606666 demonstrates that IL-4 inhibits B7-H4 (VTCN1) expression on tumor macrophages in human ovarian carcinoma. IL-4 negatively regulates B7-H4 transcription, in contrast to IL-6 and IL-10 which stimulate its expression.
Reason: The paper provides direct evidence that IL-4 negatively regulates B7-H4 expression on macrophages. This is consistent with the other GO:0045892 annotation from PMID:18579517 (also KEEP_AS_NON_CORE) and the GO:0000122 annotation from PMID:11967989 for CTGF. IL-4's ability to repress specific genes is a real but context-dependent activity, not a core function.
Supporting Evidence:
PMID:16606666
granulocyte/macrophage colony-stimulating factor and IL-4, which are limited in the tumor microenvironment, inhibit B7-H4 expression
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-6785821 |
ACCEPT |
Summary: Reactome annotation for IL-4 participation in the IL-4/IL-13 signaling pathway, specifically the SOCS5/SOCS1 binding to IL4RA reaction. IL-4 is correctly placed in the extracellular region.
Reason: IL-4 is a secreted cytokine in the extracellular region. These Reactome TAS annotations correctly reflect IL-4's participation in signaling pathway reactions as an extracellular ligand.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-6786058 |
ACCEPT |
Summary: Reactome annotation for IL-4 signaling - JAK1 binding to IL4R in IL4-bound complex.
Reason: Duplicate CC annotation from Reactome pathway. IL-4 is correctly localized to the extracellular region as part of the receptor-ligand complex.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-6786070 |
ACCEPT |
Summary: Reactome annotation for type II receptor complex assembly (IL-4 complex binding IL13RA1/TYK2).
Reason: Duplicate CC annotation from Reactome pathway. Correct localization.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-6786072 |
ACCEPT |
Summary: Reactome annotation for STAT3/STAT6 dissociation step in IL-4 signaling.
Reason: Duplicate CC annotation from Reactome pathway. Correct localization.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-6786092 |
ACCEPT |
Summary: Reactome annotation for type I receptor complex assembly (IL-4 complex binding IL2RG/JAK3).
Reason: Duplicate CC annotation from Reactome pathway. Correct localization.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-6786095 |
ACCEPT |
Summary: Reactome annotation for JAK1 phosphorylation of STAT3/STAT6 in IL-4 signaling.
Reason: Duplicate CC annotation from Reactome pathway. Correct localization.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-6786096 |
ACCEPT |
Summary: Reactome annotation for phosphorylation of IL4R/IL2RG/JAK1 components.
Reason: Duplicate CC annotation from Reactome pathway. Correct localization.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-6786101 |
ACCEPT |
Summary: Reactome annotation for IL-4 binding to IL4R/JAK2.
Reason: Duplicate CC annotation from Reactome pathway. Correct localization.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-6786124 |
ACCEPT |
Summary: Reactome annotation for STAT3/STAT6 binding to phosphorylated IL4R.
Reason: Duplicate CC annotation from Reactome pathway. Correct localization.
|
|
GO:0043011
myeloid dendritic cell differentiation
|
IDA
PMID:16116184 Galectin-9 induces maturation of human monocyte-derived dend... |
ACCEPT |
Summary: PMID:16116184 studies galectin-9 effects on monocyte-derived dendritic cells that were generated using the standard IL-4 + GM-CSF protocol. The paper uses IL-4 to differentiate monocytes into immature DCs, which are then matured by galectin-9.
Reason: IL-4 is a well-established driver of dendritic cell differentiation from monocytes. The paper directly employs IL-4 in the DC differentiation protocol. The IL-4 + GM-CSF system for DC generation is one of the most widely used in immunology.
Supporting Evidence:
PMID:16116184
Gal-9 had no or little effect on differentiation of human monocytes into immature DCs
|
|
GO:1903660
negative regulation of complement-dependent cytotoxicity
|
IMP
PMID:16034134 IL-4 and IL-13 induce protection of porcine endothelial cell... |
KEEP AS NON CORE |
Summary: PMID:16034134 demonstrates that IL-4 and IL-13 induce protection of porcine endothelial cells from killing by human complement through PI3K/Akt signaling.
Reason: The paper provides direct evidence that IL-4 protects endothelial cells from complement-mediated killing via PI3K/Akt pathway activation. This is a specialized cytoprotective effect in the xenotransplantation context, not a core immune function of IL-4.
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
PMID:16034134 IL-4 and IL-13 induce protection of porcine endothelial cell... |
KEEP AS NON CORE |
Summary: PMID:16034134 demonstrates that IL-4 protects porcine endothelial cells from apoptosis induced by TNF-alpha plus cycloheximide through PI3K/Akt signaling.
Reason: The paper provides direct evidence that IL-4 protects endothelial cells from apoptosis via PI3K/Akt pathway activation. This represents a cytoprotective effect consistent with IL-4's known anti-apoptotic signaling but in a non-immune cell context.
Supporting Evidence:
PMID:16034134
IL-4 and IL-13 can induce protection of porcine EC against killing by apoptosis and human complement through activation of the PI3K/Akt signaling pathway
|
|
GO:0010633
negative regulation of epithelial cell migration
|
IDA
PMID:11698262 Lung epithelial barrier function and wound healing are decre... |
KEEP AS NON CORE |
Summary: PMID:11698262 demonstrates that IL-4 and IL-13 decrease wound healing and migration in Calu-3 human lung epithelial cells. IL-4 treatment decreased cell migration in wound-healing assays on collagen I.
Reason: The paper provides direct evidence that IL-4 inhibits epithelial cell migration in lung epithelial cells. This is a tissue-specific effect on non-immune cells in the context of airway epithelial barrier function and wound healing, representing a pleiotropic activity rather than a core immune function.
Supporting Evidence:
PMID:11698262
In wound-healing assays of cells grown on collagen I, IL-4 and IL-13 decreased migration, whereas IFN-gamma treatment enhanced migration, compared with control cells
|
|
GO:0097028
dendritic cell differentiation
|
IDA
PMID:21149635 Monocytic cells derived from human embryonic stem cells and ... |
ACCEPT |
Summary: PMID:21149635 demonstrates that monocytic cells derived from human embryonic stem cells differentiate through pathways involving IL-4, with M2-like macrophage characteristics.
Reason: IL-4 is well-established as a key factor in dendritic cell differentiation from monocyte precursors. The paper studies monocyte differentiation pathways including IL-4 dependent steps. This is consistent with the GO:0043011 annotation.
Supporting Evidence:
PMID:21149635
monocytic cells derived from human embryonic stem cells (hESCs) and from fetal liver follow a differentiation pathway different to that of adult cells
|
|
GO:0045893
positive regulation of DNA-templated transcription
|
IDA
PMID:19346497 IFN-lambda1 (IL-29) inhibits GATA3 expression and suppresses... |
ACCEPT |
Summary: PMID:19346497 studies IFN-lambda1 inhibition of GATA3 and Th2 responses. The paper demonstrates IL-4-driven transcription in the context of Th2 cytokine gene expression. IL-4 stimulation leads to GATA3 expression and IL-4Ralpha upregulation, both of which are transcription-dependent processes.
Reason: IL-4 is a potent inducer of gene transcription through STAT6 signaling. This IDA annotation is consistent with multiple other annotations for the same term and with the known biology of IL-4.
Supporting Evidence:
PMID:19346497
Expression of Th2 cytokines (IL-4 and IL-13) was suppressed in naive and memory CD4(+) T cells by IFN-lambda1, without affecting their proliferation
|
|
GO:0032736
positive regulation of interleukin-13 production
|
IDA
PMID:19346497 IFN-lambda1 (IL-29) inhibits GATA3 expression and suppresses... |
ACCEPT |
Summary: PMID:19346497 demonstrates that IL-4-driven Th2 responses include IL-13 production, which is suppressed by IFN-lambda1. The paper shows IL-4 promotes IL-13 expression as part of the Th2 cytokine program.
Reason: IL-4 and IL-13 are co-regulated Th2 cytokines. IL-4-driven Th2 differentiation via GATA3 leads to increased IL-13 production as part of the Th2 cytokine program. The paper directly demonstrates this relationship.
Supporting Evidence:
PMID:19346497
Expression of Th2 cytokines (IL-4 and IL-13) was suppressed in naive and memory CD4(+) T cells by IFN-lambda1, without affecting their proliferation
file:human/IL4/IL4-deep-research-falcon.md
IL-4 drives Th2 differentiation (via STAT6->GATA3)
|
|
GO:0045582
positive regulation of T cell differentiation
|
IDA
PMID:20554961 Cutting edge: Type I IFN reverses human Th2 commitment and s... |
ACCEPT |
Summary: PMID:20554961 studies IL-4-driven Th2 differentiation and how type I IFN opposes it. IL-4 promotes Th2 development by inducing GATA3.
Reason: IL-4 is the canonical driver of Th2 cell differentiation from naive T cells. The paper directly studies this process and demonstrates IL-4-dependent GATA3 induction as the key mechanism of Th2 commitment.
Supporting Evidence:
PMID:20554961
IL-4 promotes Th2 development by inducing the expression of the GATA3 transcription factor, and the Th2 phenotype is stabilized by a GATA3-dependent auto-regulatory loop
|
|
GO:0045893
positive regulation of DNA-templated transcription
|
IDA
PMID:20554961 Cutting edge: Type I IFN reverses human Th2 commitment and s... |
ACCEPT |
Summary: PMID:20554961 demonstrates that IL-4 promotes transcription of GATA3 through STAT6 signaling as part of Th2 commitment.
Reason: The paper provides direct evidence that IL-4 activates GATA3 transcription through STAT6, consistent with the known transcription-activating function of IL-4.
Supporting Evidence:
PMID:20554961
IL-4 receptor signaling promotes STAT6 recruitment and phosphorylation... which ultimately regulates induction of GATA3 transcription
|
|
GO:2000553
positive regulation of T-helper 2 cell cytokine production
|
IDA
PMID:20554961 Cutting edge: Type I IFN reverses human Th2 commitment and s... |
ACCEPT |
Summary: PMID:20554961 demonstrates that IL-4 promotes Th2 cytokine production by driving GATA3-dependent Th2 differentiation and cytokine gene expression.
Reason: IL-4-driven Th2 differentiation leads to increased production of Th2 cytokines (IL-4, IL-5, IL-13). This is a core function of IL-4 as the master Th2-polarizing cytokine.
Supporting Evidence:
PMID:20554961
IL-4 promotes Th2 development by inducing the expression of the GATA3 transcription factor
|
|
GO:0045892
negative regulation of DNA-templated transcription
|
IDA
PMID:18579517 LEF-1 negatively controls interleukin-4 expression through a... |
KEEP AS NON CORE |
Summary: PMID:18579517 demonstrates that IL-4 stimulation negatively regulates expression of LEF-1 and TCF-1 transcription factors in primary T cells, creating a positive feedback loop that reinforces IL-4 gene expression by removing transcriptional repressors. This represents IL-4 negatively regulating transcription of specific target genes (LEF-1, TCF-1).
Reason: The paper provides direct evidence that IL-4 downregulates LEF-1 and TCF-1 expression, which are Wnt pathway transcription factors. This is consistent with the existing KEEP_AS_NON_CORE annotation for GO:0000122 (negative regulation of transcription by RNA polymerase II) from PMID:11967989 for CTGF. IL-4's ability to repress specific genes is a real but secondary function compared to its primary role as a transcriptional activator through STAT6.
Supporting Evidence:
PMID:18579517
we found that IL-4 stimulation possesses a negative effect on the expressions of LEF-1 and TCF-1 in primary T cells, suggesting a positive feedback effect of IL-4 on IL4 gene expression
|
|
GO:0045893
positive regulation of DNA-templated transcription
|
IDA
PMID:18579517 LEF-1 negatively controls interleukin-4 expression through a... |
ACCEPT |
Summary: PMID:18579517 demonstrates that IL-4 positively regulates its own gene expression through a feedback mechanism. IL-4 stimulation suppresses LEF-1 and TCF-1, which are negative regulators of the IL-4 promoter. Knockdown of LEF-1 by siRNA increased IL-4 mRNA expression, confirming that LEF-1 is a transcriptional repressor of IL-4. By removing this repression, IL-4 indirectly promotes transcription of IL-4 and potentially other Th2 cytokine genes.
Reason: The paper provides evidence that IL-4 positively regulates transcription through a feedback loop involving suppression of LEF-1/TCF-1 transcriptional repressors. This is consistent with the other ACCEPT annotations for GO:0045893 from IBA, IDA (PMID:19346497, PMID:20554961), which all document IL-4's well-established role as a transcriptional activator via STAT6 signaling.
Supporting Evidence:
PMID:18579517
Knockdown LEF-1 expression by LEF-1-specific small interfering RNA resulted in an increase in the IL-4 mRNA expression
PMID:18579517
we found that IL-4 stimulation possesses a negative effect on the expressions of LEF-1 and TCF-1 in primary T cells, suggesting a positive feedback effect of IL-4 on IL4 gene expression
|
|
GO:0008203
cholesterol metabolic process
|
ISS
PMID:11971948 Interleukin-4 deficiency promotes gallstone formation. |
KEEP AS NON CORE |
Summary: PMID:11971948 demonstrates that IL-4-deficient mice have a 100% incidence of gallstones and cholesterol crystals on a fat-enriched diet, compared to no gallstones in wild-type mice, suggesting IL-4 plays a role in cholesterol metabolism. ISS from mouse IL-4 (P07750).
Reason: The paper provides genetic evidence that IL-4 deficiency predisposes to gallstone formation and altered cholesterol metabolism. However, this is a pleiotropic downstream effect rather than a core immune function of IL-4.
Supporting Evidence:
PMID:11971948
IL-4(-/-) mice had a 100% incidence of gallstones and cholesterol crystals
|
|
GO:0030890
positive regulation of B cell proliferation
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: IL-4 promotes B cell proliferation as one of its defining functions. Originally named B-cell stimulatory factor 1 (BSF-1) for this activity. Transferred from mouse IL-4 (P07750).
Reason: B cell proliferation is a core function of IL-4. It was originally identified as BSF-1 precisely for its B cell growth-promoting activity. The ISS from mouse is well-supported by extensive human data.
Supporting Evidence:
file:human/IL4/IL4-uniprot.txt
AltName...B-cell stimulatory factor 1; Short=BSF-1
|
|
GO:0042102
positive regulation of T cell proliferation
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: IL-4 promotes T cell proliferation, particularly of Th2-committed cells. Also known as lymphocyte stimulatory factor 1. Transferred from mouse IL-4 (P07750).
Reason: T cell proliferation promotion is a known function of IL-4, consistent with its alternative name as lymphocyte stimulatory factor 1. The ISS from mouse is well-supported.
Supporting Evidence:
file:human/IL4/IL4-uniprot.txt
AltName...Lymphocyte stimulatory factor 1
|
|
GO:0043066
negative regulation of apoptotic process
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: IL-4 has well-documented anti-apoptotic effects, promoting survival of B cells, T cells, and other immune cells through PI3K/Akt signaling. Transferred from mouse IL-4 (P07750).
Reason: While IL-4 has anti-apoptotic effects through IRS-2/PI3K signaling, this is a secondary consequence of its signaling rather than a core function. The annotation is not incorrect but represents a downstream effect.
|
|
GO:0045348
positive regulation of MHC class II biosynthetic process
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: IL-4 induces MHC class II expression on B cells, enhancing their antigen-presenting capacity. This is one of IL-4's original defining functions. Transferred from mouse IL-4 (P07750).
Reason: MHC class II upregulation on B cells by IL-4 is one of the earliest described functions of this cytokine and is directly documented in the UniProt function annotation. The ISS from mouse is well-supported by human data.
Supporting Evidence:
file:human/IL4/IL4-uniprot.txt
Induces the expression of class II MHC molecules on resting B-cells
|
|
GO:0045671
negative regulation of osteoclast differentiation
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: IL-4 has been reported to inhibit osteoclast differentiation, likely through anti-inflammatory effects that oppose RANKL signaling. Transferred from mouse IL-4 (P07750).
Reason: While IL-4 may inhibit osteoclastogenesis, this is a specialized tissue-specific effect rather than a core immune function. The ISS annotation is from mouse data and represents a pleiotropic activity.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: IL-4 activates RNA polymerase II-dependent transcription through STAT6-mediated signaling. Transferred from mouse IL-4 (P07750).
Reason: This is well-supported by the IGI annotation with the same term from PMID:12574355 and by the known mechanism of STAT6-dependent gene activation. The ISS from mouse is consistent with human data.
|
|
GO:0048295
positive regulation of isotype switching to IgE isotypes
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: IL-4 is the primary cytokine that drives B cell class switch recombination to IgE. This is arguably the most important and specific function of IL-4 in adaptive immunity, and the basis for anti-IL-4 therapy in allergic disease. Transferred from mouse IL-4 (P07750).
Reason: IgE class switching is THE defining function of IL-4 in B cell biology. IL-4 induces germline epsilon transcription through STAT6 signaling, which is required for IgE class switch recombination. This is the mechanistic basis for dupilumab therapy in allergic diseases.
Supporting Evidence:
file:human/IL4/IL4-uniprot.txt
Enhances both secretion and cell surface expression of IgE and IgG1
file:human/IL4/IL4-deep-research-falcon.md
IL-4 drives...B-cell proliferation and class-switch recombination to IgE
|
|
GO:0048304
positive regulation of isotype switching to IgG isotypes
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: IL-4 promotes IgG1 (in mouse) and IgG4 (in human) class switching. Transferred from mouse IL-4 (P07750).
Reason: IL-4 promotes IgG class switching in addition to IgE switching. In humans, IL-4 drives switching to IgG4; in mice, to IgG1. This is a well-established function.
Supporting Evidence:
file:human/IL4/IL4-uniprot.txt
Enhances both secretion and cell surface expression of IgE and IgG1
|
|
GO:0050776
regulation of immune response
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: IL-4 regulates immune responses, particularly type 2 immunity. Transferred from mouse IL-4 (P07750). Duplicate of the IBA annotation.
Reason: Duplicate of the IBA annotation with ISS evidence. Both are correct and complementary.
|
|
GO:0005136
interleukin-4 receptor binding
|
TAS
PMID:3016727 Isolation and characterization of a human interleukin cDNA c... |
ACCEPT |
Summary: PMID:3016727 is the original paper by Yokota et al. (1986) reporting the cloning and characterization of human IL-4 cDNA, including its B-cell and T-cell stimulating activities through receptor binding.
Reason: This is the seminal paper identifying human IL-4. The TAS annotation for IL-4 receptor binding from the original characterization paper is historically and scientifically well-supported.
Supporting Evidence:
PMID:3016727
Supernatant of COS-7 monkey cells transfected with the human cDNA clone stimulated proliferation of human helper T-cell clones and of anti-IgM-activated human B cells, two properties of mouse BSF-1 on mouse cells
file:human/IL4/IL4-uniprot.txt
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION...Isolation and characterization of a human interleukin cDNA clone, homologous to mouse B-cell stimulatory factor 1
|
|
GO:0005615
extracellular space
|
TAS
PMID:3016727 Isolation and characterization of a human interleukin cDNA c... |
ACCEPT |
Summary: The original IL-4 cloning paper by Yokota et al. (1986) characterizes IL-4 as a secreted protein with a putative signal peptide and extracellular activity.
Reason: Correct localization annotation from the original characterization paper.
Supporting Evidence:
PMID:3016727
The human cDNA contains a single open reading frame encoding a protein of 153 amino acid residues including a putative signal peptide
|
|
GO:0006955
immune response
|
TAS
PMID:3016727 Isolation and characterization of a human interleukin cDNA c... |
ACCEPT |
Summary: IL-4 was characterized as an immune response cytokine in the original cloning paper, showing B-cell and T-cell stimulating activities.
Reason: IL-4 is fundamentally an immune response mediator. The TAS annotation from the original characterization paper is correct.
Supporting Evidence:
PMID:3016727
Supernatant of COS-7 monkey cells transfected with the human cDNA clone stimulated proliferation of human helper T-cell clones and of anti-IgM-activated human B cells
|
|
GO:0005136
interleukin-4 receptor binding
|
TAS
PMID:11418631 The distinct roles of T cell-derived cytokines and a novel f... |
ACCEPT |
Summary: PMID:11418631 studies IL-4 receptor-mediated signaling in the context of germinal center B cell differentiation, demonstrating that IL-4 acts through its receptor to direct GC-B cell fate toward memory B cells.
Reason: IL-4 receptor binding is the core molecular function. The paper demonstrates IL-4 receptor-mediated biological effects. Duplicate with different reference is acceptable.
Supporting Evidence:
PMID:11418631
IL-4 directs GC-B cells to differentiate into memory B cells, whereas IL-10 steers them into PC
|
|
GO:0005615
extracellular space
|
TAS
PMID:11418631 The distinct roles of T cell-derived cytokines and a novel f... |
ACCEPT |
Summary: PMID:11418631 studies the effects of T cell-derived cytokines including secreted IL-4 on germinal center B cell differentiation, consistent with IL-4 activity in the extracellular space.
Reason: Correct localization. IL-4 is a secreted cytokine that acts in the extracellular space. Duplicate with different reference is acceptable.
Supporting Evidence:
PMID:11418631
cytokines secreted by activated T cells determined the pathway of GC-B cell differentiation
|
|
GO:0008083
growth factor activity
|
NAS
PMID:11418631 The distinct roles of T cell-derived cytokines and a novel f... |
KEEP AS NON CORE |
Summary: PMID:11418631 demonstrates that IL-4 and FDC signals provide growth-promoting signals for germinal center B cells. IL-4 has growth factor activity for B and T cells (originally named BSF-1).
Reason: While IL-4 has growth-promoting activity for lymphocytes, its primary molecular function is better described as cytokine activity and IL-4 receptor binding. Growth factor activity is a secondary characterization.
Supporting Evidence:
PMID:11418631
FDC/HK cells do not direct either pathway, but provide signals for proliferation of GC-B cells
|
|
GO:0030183
B cell differentiation
|
TAS
PMID:11418631 The distinct roles of T cell-derived cytokines and a novel f... |
ACCEPT |
Summary: PMID:11418631 directly demonstrates that IL-4 directs germinal center B cells to differentiate into memory B cells, while IL-10 steers them toward plasma cells.
Reason: B cell differentiation is a core function of IL-4. The paper provides direct evidence for IL-4's role in directing GC-B cell differentiation pathways.
Supporting Evidence:
PMID:11418631
IL-4 directs GC-B cells to differentiate into memory B cells, whereas IL-10 steers them into PC
file:human/IL4/IL4-uniprot.txt
Enhances both secretion and cell surface expression of IgE and IgG1
|
|
GO:0042092
type 2 immune response
|
TAS
PMID:11676128 [Inflammatory cytokines (IL-4, IL-5 and IL-13)]. |
ACCEPT |
Summary: PMID:11676128 reviews IL-4, IL-5, and IL-13 as Th2 cytokines pivotal in regulating the allergic phenotype, IgE response, and inflammatory cell-mediated function. IL-4 is THE defining cytokine of type 2 immune responses.
Reason: Type 2 immune response is the most accurate high-level description of IL-4's biological role. IL-4 is the master regulator of type 2 immunity.
Supporting Evidence:
PMID:11676128
Th2 cytokines, such as IL-4, IL-5 and IL-13, are pivotal in regulating the allergic phenotype, the IgE response or the inflammatory cell-mediated function
file:human/IL4/IL4-deep-research-falcon.md
IL-4 is a central driver of type-2 endotypes (eosinophilic/allergic) across airway and barrier diseases
|
|
GO:0045191
regulation of isotype switching
|
TAS
PMID:11418631 The distinct roles of T cell-derived cytokines and a novel f... |
ACCEPT |
Summary: PMID:11418631 studies the role of T cell-derived cytokines including IL-4 in germinal center B cell differentiation, which includes isotype switching. IL-4 is the primary cytokine regulating class switch recombination to IgE and IgG4 in humans.
Reason: Isotype switching regulation is a core function of IL-4. More specific child terms (IgE and IgG switching) are also annotated. This general term appropriately captures the broader regulatory role.
Supporting Evidence:
PMID:11418631
IL-4 directs GC-B cells to differentiate into memory B cells, whereas IL-10 steers them into PC
file:human/IL4/IL4-uniprot.txt
Enhances both secretion and cell surface expression of IgE and IgG1
|
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: IL4 (UniProt P05112) – human Interleukin-4 (IL‑4)
Target verification and identity
- Gene/protein checked: IL4 encodes human IL‑4, a secreted cytokine of the IL‑4/IL‑13 family. Contemporary structure-guided engineering confirms IL‑4’s four-helix bundle topology and three conserved disulfide bonds (Cys3–Cys127, Cys24–Cys65, Cys46–Cys99), aligning with UniProt’s family/domain annotations (ACS Omega, 2023; https://doi.org/10.1021/acsomega.3c00726, Jul 2023) (thomas2023designofglycoengineered pages 28-31).
- Organism: Homo sapiens confirmed throughout cited 2023–2024 literature (thomas2023designofglycoengineered pages 28-31).
Key concepts and definitions with current understanding
- Molecular identity and structure: IL‑4 is a short-chain class I cytokine adopting a four‑α‑helix bundle stabilized by three disulfides. Structure–function mapping identifies site I on helices A–C as the IL‑4Rα interface (key residues Glu9, Arg88) and site II mediating recruitment of γc or IL‑13Rα1 to form signaling complexes (ACS Omega, 2023; https://doi.org/10.1021/acsomega.3c00726, Jul 2023) (thomas2023designofglycoengineered pages 28-31).
- Receptor usage and signaling: IL‑4 signals via two receptor complexes: type I (IL‑4Rα/γc) largely on hematopoietic cells and type II (IL‑4Rα/IL‑13Rα1) on many non‑hematopoietic cells. JAK–STAT is canonical: type I (primarily JAK1/JAK3) and type II (JAK2/TYK2 reported), converging on STAT6; IRS‑2→PI3K/MAPK pathways also contribute to survival/proliferation programs (Exploration of Immunology, 2025; https://doi.org/10.37349/ei.2025.1003183, Feb 2025) (wong2025theroleof pages 11-13). Mechanistic reviews in asthma corroborate STAT6-centric signaling in type‑2 immunity (Biomedicines, 2025; https://doi.org/10.3390/biomedicines13061342, May 2025) (reza2025inflammationinasthma pages 7-8, reza2025inflammationinasthma pages 13-14).
- Cellular sources: Major producers include Th2 cells, T follicular helper (Tfh) cells, group 2 innate lymphoid cells (ILC2s), basophils, mast cells, and, context‑dependently, eosinophils; basophils are highlighted as early IL‑4 sources in allergic priming (Biomolecules, 2024; https://doi.org/10.3390/biom14050546, May 2024) (nakagome2024thepossibleroles pages 5-7). Additional overviews emphasize Th2/mast cell/basophil sources and effector actions (Exploration of Immunology, 2025; https://doi.org/10.37349/ei.2025.1003183, Feb 2025) (wong2025theroleof pages 11-13).
- Primary functions: IL‑4 drives Th2 differentiation (via STAT6→GATA3), B‑cell proliferation and class‑switch recombination to IgE, and alternative (M2) macrophage activation; IL‑13 overlaps but acts more directly on structural cells (epithelium, smooth muscle, fibroblasts) (Biomolecules, 2024; https://doi.org/10.3390/biom14050546, May 2024) (nakagome2024thepossibleroles pages 5-7). IL‑4/IL‑13 redundancy in IgE biology supports shared‑receptor therapeutic strategies (ACS Omega, 2023; https://doi.org/10.1021/acsomega.3c00726, Jul 2023) (thomas2023designofglycoengineered pages 28-31).
- Localization: IL‑4 is secreted and acts via cell‑surface IL‑4Rα‑containing receptors; downstream signaling is intracellular (wong2025theroleof pages 11-13, thomas2023designofglycoengineered pages 28-31).
Recent developments and latest research (2023–2024 priority)
- Structural and engineering advances: Structure‑guided mutational and glycoengineering studies refined IL‑4’s receptor‑binding sites and produced antagonistic IL‑4 variants, supporting domain‑level understanding and drug design. The 2023 ACS Omega study details site I (IL‑4Rα) and site II (γc/IL‑13Rα1) determinants and demonstrates glycan attachment strategies that convert IL‑4 into long‑lived antagonists, highlighting translational avenues beyond antibodies (ACS Omega, 2023; https://doi.org/10.1021/acsomega.3c00726, Jul 2023) (thomas2023designofglycoengineered pages 28-31).
- Immunobiology of type‑2 airway disease: A 2024 review synthesizes IL‑4/IL‑13 roles in severe eosinophilic asthma, including DC‑mediated Th2 priming, effects on goblet cell differentiation/mucus production, smooth muscle hyperreactivity, and airway remodeling. It emphasizes basophils/ILC2s as critical contributors and documents clinical efficacy of IL‑4Rα blockade (Biomolecules, 2024; https://doi.org/10.3390/biom14050546, May 2024) (nakagome2024thepossibleroles pages 5-7).
Current applications and real‑world implementations
- Rationale for dual‑pathway blockade: Because IL‑4 and IL‑13 share IL‑4Rα and have overlapping functions in allergic disease, shared‑receptor inhibition (e.g., dupilumab) outperforms single‑cytokine strategies that historically under‑performed (e.g., pascolizumab, some anti‑IL‑13 programs). 2023 structure‑guided analyses and therapeutic reviews converge on IL‑4Rα as the optimal node (ACS Omega, 2023; https://doi.org/10.1021/acsomega.3c00726, Jul 2023) (thomas2023designofglycoengineered pages 28-31).
- Dupilumab (anti‑IL‑4Rα): mechanism and clinical translation
- Mechanism: Human IgG4 mAb targeting IL‑4Rα to block both IL‑4 and IL‑13 signaling, suppressing STAT6‑dependent type‑2 programs (Frontiers in Pharmacology, 2025; https://doi.org/10.3389/fphar.2025.1631321, Aug 2025) (ameer2025exploringdupilumabfor pages 2-3).
- Asthma (moderate–severe, T2‑high and selected T2‑low): Pooled/long‑term clinical data summarized in 2025 reviews report sizable reductions in severe exacerbations and improvements in pre‑bronchodilator FEV1. Quantitatively, patients with baseline blood eosinophils ≥300/µL experienced a 65.8% reduction in annualized severe exacerbations; in OCS‑dependent asthma, oral glucocorticoid use decreased by 70.1%. Long‑term extensions showed sustained efficacy and a safety profile notable for transient blood eosinophilia (~4.1%) (Biomedicines, 2025; https://doi.org/10.3390/biomedicines13061342, May 2025) (reza2025inflammationinasthma pages 14-16, reza2025inflammationinasthma pages 13-14). Although these summaries consolidate earlier pivotal trials, they reflect continued clinical adoption into 2023–2024.
- CRSwNP: Contemporary therapeutic overviews and cost‑effectiveness analyses (2023) position dupilumab as effective for T2‑biased nasal polyposis in line with its airway biology; 2024 field reviews of T2 inflammation in CRSwNP recapitulate IL‑4/IL‑13’s pathobiology underpinning efficacy (Frontiers in Immunology, 2024; https://doi.org/10.3389/fimmu.2024.1356298, Apr 2024) (varut2025targetedbiologictherapies pages 11-13).
- Atopic dermatitis and EoE: Cross‑indication efficacy is consistent with IL‑4/IL‑13’s central role in barrier dysfunction and type‑2 inflammation; recent reviews detail broad improvements in AD and EoE with IL‑4Rα blockade as of 2023–2024 (ACS Omega, 2023; https://doi.org/10.1021/acsomega.3c00726, Jul 2023) (thomas2023designofglycoengineered pages 28-31) and asthma‑focused synopses with EoE notes (Biomedicines, 2025; https://doi.org/10.3390/biomedicines13061342, May 2025) (reza2025inflammationinasthma pages 7-8, reza2025inflammationinasthma pages 14-16).
- Earlier/alternative IL‑4 pathway agents
- Pitrakinra (recombinant IL‑4 mutein; IL‑4/IL‑13 signaling antagonist): Phase 2a allergen‑challenge studies showed attenuated FEV1 decline vs placebo (study examples: maximum FEV1 decrease 17.1% vs 23.1%; average decrease 4.4% vs 15.9%), but development did not proceed to approval (Biomedicines, 2025; https://doi.org/10.3390/biomedicines13061342, May 2025) (reza2025inflammationinasthma pages 14-16, massey2021recentadvancesin pages 4-6).
- Pascolizumab (anti‑IL‑4 mAb): clinical efficacy in asthma was insufficient, and the program was discontinued; results, together with variable anti‑IL‑13 outcomes, support targeting IL‑4Rα rather than a single cytokine (Biomedicines, 2025; https://doi.org/10.3390/biomedicines13061342, May 2025) (massey2021recentadvancesin pages 4-6, reza2025inflammationinasthma pages 14-16).
Expert opinions and authoritative syntheses
- Field reviews integrating immunology and translation (2024–2025) concur that IL‑4 is a central driver of type‑2 endotypes (eosinophilic/allergic) across airway and barrier diseases, and that IL‑4Rα blockade delivers clinically meaningful benefit across multiple indications by intercepting redundant IL‑4/IL‑13 signaling (Biomolecules, 2024; https://doi.org/10.3390/biom14050546, May 2024) (nakagome2024thepossibleroles pages 5-7); (Frontiers in Immunology, 2024; https://doi.org/10.3389/fimmu.2024.1356298, Apr 2024) (varut2025targetedbiologictherapies pages 11-13); (ACS Omega, 2023; https://doi.org/10.1021/acsomega.3c00726, Jul 2023) (thomas2023designofglycoengineered pages 28-31).
Relevant statistics and data from recent studies
- Asthma (clinical outcomes with anti‑IL‑4Rα):
- Annualized severe exacerbations reduced by 65.8% in patients with eosinophils ≥300/µL; oral glucocorticoid dose reduced by 70.1% in OCS‑dependent cohorts; improvements in pre‑BD FEV1 and biomarkers (FeNO↓; transient eosinophils↑). Long‑term extensions reported TEAEs in ~76–95% (expected for chronic biologic therapy) with ~4% blood eosinophilia and rare serious AEs (Biomedicines, 2025; https://doi.org/10.3390/biomedicines13061342, May 2025) (reza2025inflammationinasthma pages 14-16, reza2025inflammationinasthma pages 13-14).
- Pitrakinra (phase 2a allergen‑challenge protection): maximum FEV1 decrease 17.1% vs 23.1% (placebo) and average FEV1 decrease 4.4% vs 15.9% (placebo), illustrating target engagement but limited development (Biomedicines, 2025; https://doi.org/10.3390/biomedicines13061342, May 2025) (reza2025inflammationinasthma pages 14-16).
Functional annotation summary (mechanism, pathways, and localization)
- Biochemical role: IL‑4 is a secreted cytokine that binds IL‑4Rα-containing heterodimeric receptors (type I or II) at the plasma membrane to initiate intracellular JAK–STAT6 signaling. It instructs Th2 differentiation (GATA3 program), promotes B‑cell class switch to IgE, and polarizes macrophages toward M2 states; IL‑13 shares downstream pathways, with greater action on non‑hematopoietic targets (Biomolecules, 2024; https://doi.org/10.3390/biom14050546, May 2024) (nakagome2024thepossibleroles pages 5-7); (Exploration of Immunology, 2025; https://doi.org/10.37349/ei.2025.1003183, Feb 2025) (wong2025theroleof pages 11-13).
- Cellular/subcellular localization: IL‑4 is secreted and functions in the extracellular space; signaling occurs at/through cell‑surface IL‑4R complexes with cytoplasmic JAKs and STAT6 effectors (wong2025theroleof pages 11-13, thomas2023designofglycoengineered pages 28-31).
- Disease pathways: IL‑4 is a master regulator in type‑2 inflammatory diseases—atopy, asthma, atopic dermatitis, CRSwNP, and eosinophilic esophagitis—through effects on antigen presentation, IgE production, eosinophil recruitment, epithelial remodeling, mucus hypersecretion, and fibrosis (Biomolecules, 2024; https://doi.org/10.3390/biom14050546, May 2024) (nakagome2024thepossibleroles pages 5-7); (Frontiers in Immunology, 2024; https://doi.org/10.3389/fimmu.2024.1356298, Apr 2024) (varut2025targetedbiologictherapies pages 11-13).
Notes on evidence prioritization and limitations
- 2023–2024 sources prioritized: ACS Omega (2023) provided structural and therapeutic‑engineering specificity; Biomolecules (2024) and Frontiers in Immunology (2024) covered IL‑4/IL‑13 biology in airway disease and CRSwNP. Quantitative dupilumab outcomes in asthma are summarized in 2025 peer‑reviewed syntheses that consolidate earlier pivotal trials with continuing real‑world/extension data (Biomedicines, 2025; Frontiers in Pharmacology, 2025); exact 2023–2024 trial readouts are consistent with these summaries but not all primary trial URLs were captured in the retrieved corpus (reza2025inflammationinasthma pages 7-8, reza2025inflammationinasthma pages 14-16, ameer2025exploringdupilumabfor pages 2-3, reza2025inflammationinasthma pages 13-14).
Citations
- ACS Omega, 2023 (structural and antagonist engineering of IL‑4; URL: https://doi.org/10.1021/acsomega.3c00726; published Jul 2023) (thomas2023designofglycoengineered pages 28-31).
- Biomolecules, 2024 (IL‑4/IL‑13 roles in eosinophilic asthma; URL: https://doi.org/10.3390/biom14050546; published May 2024) (nakagome2024thepossibleroles pages 5-7).
- Frontiers in Immunology, 2024 (IL‑4/IL‑13 pathway in CRSwNP; URL: https://doi.org/10.3389/fimmu.2024.1356298; published Apr 2024) (varut2025targetedbiologictherapies pages 11-13).
- Exploration of Immunology, 2025 (IL‑4 receptor complexes and signaling breadth; URL: https://doi.org/10.37349/ei.2025.1003183; published Feb 2025) (wong2025theroleof pages 11-13).
- Biomedicines, 2025 (asthma immunology and dupilumab outcomes; URL: https://doi.org/10.3390/biomedicines13061342; published May 2025) (reza2025inflammationinasthma pages 7-8, reza2025inflammationinasthma pages 14-16, reza2025inflammationinasthma pages 13-14).
- Frontiers in Pharmacology, 2025 (dupilumab pharmacology/mechanism; URL: https://doi.org/10.3389/fphar.2025.1631321; published Aug 2025) (ameer2025exploringdupilumabfor pages 2-3).
References
(thomas2023designofglycoengineered pages 28-31): Sarah Thomas, Juliane E. Fiebig, Eva-Maria Kuhn, Dominik S. Mayer, Sebastian Filbeck, Werner Schmitz, Markus Krischke, Roswitha Gropp, and Thomas D. Mueller. Design of glycoengineered il-4 antagonists employing chemical and biosynthetic glycosylation. ACS Omega, 8:24841-24852, Jul 2023. URL: https://doi.org/10.1021/acsomega.3c00726, doi:10.1021/acsomega.3c00726. This article has 5 citations and is from a peer-reviewed journal.
(wong2025theroleof pages 11-13): Rachel Si-Yin Wong, Timothy Tan, Alexander Shao-Rong Pang, and Dinesh Kumar Srinivasan. The role of cytokines in wound healing: from mechanistic insights to therapeutic applications. Exploration of Immunology, Feb 2025. URL: https://doi.org/10.37349/ei.2025.1003183, doi:10.37349/ei.2025.1003183. This article has 23 citations.
(reza2025inflammationinasthma pages 7-8): Mohammad Irshad Reza and Nilesh S Ambhore. Inflammation in asthma: mechanistic insights and the role of biologics in therapeutic frontiers. Biomedicines, May 2025. URL: https://doi.org/10.3390/biomedicines13061342, doi:10.3390/biomedicines13061342. This article has 8 citations and is from a poor quality or predatory journal.
(reza2025inflammationinasthma pages 13-14): Mohammad Irshad Reza and Nilesh S Ambhore. Inflammation in asthma: mechanistic insights and the role of biologics in therapeutic frontiers. Biomedicines, May 2025. URL: https://doi.org/10.3390/biomedicines13061342, doi:10.3390/biomedicines13061342. This article has 8 citations and is from a poor quality or predatory journal.
(nakagome2024thepossibleroles pages 5-7): Kazuyuki Nakagome and Makoto Nagata. The possible roles of il-4/il-13 in the development of eosinophil-predominant severe asthma. Biomolecules, 14:546, May 2024. URL: https://doi.org/10.3390/biom14050546, doi:10.3390/biom14050546. This article has 68 citations and is from a poor quality or predatory journal.
(ameer2025exploringdupilumabfor pages 2-3): Omar Z. Ameer, Ghaith K. Mansour, Raghad S. Al-Amoudi, and Fahmi M. Abu‐Owaimer. Exploring dupilumab for asthma: from mechanistic insights to clinical outcomes, safety, and cost-effectiveness. Frontiers in Pharmacology, Aug 2025. URL: https://doi.org/10.3389/fphar.2025.1631321, doi:10.3389/fphar.2025.1631321. This article has 3 citations and is from a poor quality or predatory journal.
(reza2025inflammationinasthma pages 14-16): Mohammad Irshad Reza and Nilesh S Ambhore. Inflammation in asthma: mechanistic insights and the role of biologics in therapeutic frontiers. Biomedicines, May 2025. URL: https://doi.org/10.3390/biomedicines13061342, doi:10.3390/biomedicines13061342. This article has 8 citations and is from a poor quality or predatory journal.
(varut2025targetedbiologictherapies pages 11-13): Renata Maria Văruț, Dop Dalia, Kristina Radivojevic, Diana Maria Trasca, George-Alin Stoica, Niculescu Stefan Adrian, Niculescu Elena Carmen, and Cristina Elena Singer. Targeted biologic therapies in severe asthma: mechanisms, biomarkers, and clinical applications. Pharmaceuticals, 18:1021, Jul 2025. URL: https://doi.org/10.3390/ph18071021, doi:10.3390/ph18071021. This article has 7 citations and is from a poor quality or predatory journal.
(massey2021recentadvancesin pages 4-6): Oliver Massey and Cenk Suphioglu. Recent advances in the inhibition of the il-4 cytokine pathway for the treatment of allergen-induced asthma. International Journal of Molecular Sciences, 22:13655, Dec 2021. URL: https://doi.org/10.3390/ijms222413655, doi:10.3390/ijms222413655. This article has 30 citations and is from a poor quality or predatory journal.
id: P05112
gene_symbol: IL4
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: 'Interleukin-4 (IL-4) is a secreted four-helix bundle cytokine of the
IL-4/IL-13 family, produced primarily by Th2 cells, basophils, mast cells, eosinophils,
and group 2 innate lymphoid cells (ILC2s). It functions as the master regulator
of type 2 immunity by binding the IL-4 receptor alpha chain (IL4RA) and signaling
through two receptor complexes: the type I complex (IL4RA/IL2RG) on hematopoietic
cells, and the type II complex (IL4RA/IL13RA1) on non-hematopoietic and some hematopoietic
cells. IL-4 signals canonically through JAK1/JAK3-STAT6, leading to GATA3 induction
that drives Th2 differentiation, B cell class switch recombination to IgE and IgG4,
MHC class II upregulation on B cells, and M2 macrophage polarization. IL-4 also
activates IRS-2/PI3K pathways contributing to cell survival and proliferation. It
is a central mediator of allergic inflammation, anti-helminth defense, and various
immune regulatory processes. The protein has three disulfide bonds (Cys3-Cys127,
Cys24-Cys65, Cys46-Cys99) and one N-glycosylation site (Asn62). An alternatively
spliced isoform (IL-4delta2) lacking exon 2 acts as a natural antagonist.'
alternative_products:
- name: 1 (Long)
id: P05112-1
- name: 2 (Short, IL-4delta2)
id: P05112-2
sequence_note: VSP_002672
existing_annotations:
- term:
id: GO:0035771
label: interleukin-4-mediated signaling pathway
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: IL-4 is the defining ligand of the IL-4-mediated signaling pathway. It
binds IL4RA to initiate JAK/STAT6 signaling cascades that drive Th2 differentiation,
IgE class switching, and other downstream effects. This is a core biological
process for IL-4.
action: ACCEPT
reason: This is the most specific and appropriate BP term for IL-4 as the initiating
ligand of this pathway. The IBA annotation is phylogenetically well-supported
and represents the central biological role of the protein. Extensively documented
in the deep research and UniProt function annotation.
supported_by:
- reference_id: file:human/IL4/IL4-deep-research-falcon.md
supporting_text: IL-4 signals via two receptor complexes...type I (IL-4R-alpha/gamma-c)
largely on hematopoietic cells and type II (IL-4R-alpha/IL-13R-alpha1) on
many non-hematopoietic cells. JAK-STAT is canonical...converging on STAT6
- reference_id: PMID:12574355
supporting_text: IL-4-dependent AID induction was inhibited by a dominant-negative
STAT6, indicating that IL-4 induced AID expression via the Janus kinase (JAK)/STAT6
signaling pathway
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: IL-4 signaling via STAT6 activates transcription of numerous target genes
including GATA3, germline Ig epsilon transcripts, CD23, and MHC class II genes.
This is a well-established downstream consequence of IL-4 signaling.
action: ACCEPT
reason: IL-4 is well-documented as a transcriptional activator through STAT6-mediated
signaling. The IBA annotation is broadly correct and represents a core downstream
activity. This is a general term but appropriate for a cytokine with pleiotropic
transcriptional effects.
supported_by:
- reference_id: PMID:12574355
supporting_text: IL-4 was able to induce AID expression in human primary B cells
and B cell lines, and IL-4-induced AID expression was further enhanced by
CD40 signaling
- reference_id: PMID:20554961
supporting_text: IL-4 promotes Th2 development by inducing the expression of
the GATA3 transcription factor
- term:
id: GO:0050776
label: regulation of immune response
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: IL-4 is a major immunoregulatory cytokine that shapes adaptive immune
responses by driving Th2 polarization, B cell activation and class switching,
and M2 macrophage polarization, while simultaneously suppressing Th1 responses.
action: ACCEPT
reason: This is a broad but accurate term for IL-4. As a key immunoregulatory
cytokine, IL-4 fundamentally regulates immune responses. The IBA annotation
is well-supported. While more specific terms exist and are also annotated, this
general term appropriately captures the broad immunoregulatory role.
supported_by:
- reference_id: file:human/IL4/IL4-deep-research-falcon.md
supporting_text: IL-4 is a central driver of type-2 endotypes (eosinophilic/allergic)
across airway and barrier diseases
- term:
id: GO:0050728
label: negative regulation of inflammatory response
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: IL-4 has well-documented anti-inflammatory properties, particularly in
suppressing pro-inflammatory Th1/M1 macrophage responses, inhibiting TNF-alpha
production, and promoting M2 (anti-inflammatory) macrophage polarization. This
is a core function of IL-4 in immune regulation.
action: ACCEPT
reason: IL-4 is a canonical anti-inflammatory cytokine that promotes M2 macrophage
polarization and suppresses pro-inflammatory cytokine production. The IBA annotation
is phylogenetically well-supported and consistent with extensive experimental
evidence.
supported_by:
- reference_id: file:human/IL4/IL4-deep-research-falcon.md
supporting_text: IL-4 drives...alternative (M2) macrophage activation
- term:
id: GO:0005125
label: cytokine activity
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: IL-4 is by definition a cytokine - a secreted signaling molecule that
modulates immune cell behavior. This is the most fundamental molecular function
classification for IL-4.
action: ACCEPT
reason: IL-4 is unambiguously a cytokine. The IEA annotation from UniProt keyword
mapping is correct and consistent with the IDA annotation for the same term.
This broad MF term is appropriate alongside the more specific GO:0005136 (interleukin-4
receptor binding).
supported_by:
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: Cytokine secreted primarily by mast cells, T-cells, eosinophils,
and basophils that plays a role in regulating antibody production, hematopoiesis
and inflammation
- term:
id: GO:0005126
label: cytokine receptor binding
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: IL-4 binds cytokine receptors (IL4RA, IL13RA1) as part of its signaling
mechanism. This is a parent term of the more specific GO:0005136 (interleukin-4
receptor binding).
action: ACCEPT
reason: This is a correct but less specific parent term. Since the more specific
GO:0005136 is also annotated, this IEA annotation is redundant but not incorrect.
Acceptable as an IEA capturing the broader category.
supported_by:
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: Upon binding to IL4, IL4R receptor dimerizes either with the
common IL2R gamma chain/IL2RG...or with the IL13RA1
- term:
id: GO:0005136
label: interleukin-4 receptor binding
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: IL-4 specifically binds the IL-4 receptor alpha chain (IL4RA) at its
site I interface (helices A-C, key residues Glu9/Arg88). This is the most specific
and informative MF term for IL-4.
action: ACCEPT
reason: This is the core molecular function of IL-4 as a ligand. The IEA annotation
from InterPro domain mapping is correct and supported by extensive structural
and biochemical data, including crystal structures of the IL-4/IL4RA complex.
supported_by:
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: Interacts with IL4R...Interacts with IL13RA1
- reference_id: file:human/IL4/IL4-deep-research-falcon.md
supporting_text: structure-function mapping identifies site I on helices A-C
as the IL-4R-alpha interface (key residues Glu9, Arg88)
- term:
id: GO:0005576
label: extracellular region
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: IL-4 is a secreted cytokine that functions in the extracellular region.
UniProt annotates it as Secreted.
action: ACCEPT
reason: IL-4 is a secreted protein with a signal peptide (residues 1-24). The
extracellular region localization is correct and well-established. This is broader
than GO:0005615 (extracellular space) but acceptable as an IEA annotation.
supported_by:
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Secreted'
- term:
id: GO:0005615
label: extracellular space
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: IL-4 is secreted into the extracellular space where it functions as a
paracrine/ autocrine signaling molecule.
action: ACCEPT
reason: Correct IEA annotation consistent with the IDA evidence for the same term.
IL-4 is a secreted cytokine that acts in the extracellular space.
supported_by:
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Secreted'
- term:
id: GO:0006955
label: immune response
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: IL-4 is a key mediator of immune responses, particularly type 2 immunity.
This is a very broad BP term.
action: ACCEPT
reason: This is a very general but correct IEA annotation. IL-4 is fundamentally
an immune response mediator. More specific terms are also annotated. Acceptable
as a broad IEA classification.
supported_by:
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: Cytokine secreted primarily by mast cells, T-cells, eosinophils,
and basophils that plays a role in regulating antibody production, hematopoiesis
and inflammation, and the development of effector T-cell responses
- term:
id: GO:0008083
label: growth factor activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: IL-4 was historically known as B-cell stimulatory factor 1 (BSF-1) and
promotes proliferation of B and T cells. However, its primary identity is as
a cytokine rather than a classical growth factor.
action: KEEP_AS_NON_CORE
reason: While IL-4 does promote cell proliferation (B cells, T cells), its primary
molecular function is better described as cytokine activity (GO:0005125) and
IL-4 receptor binding (GO:0005136). Growth factor activity is a secondary characterization.
The UniProt keyword mapping that generated this annotation reflects the historical
BSF-1 naming but is not the most informative descriptor.
supported_by:
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: AltName...B-cell stimulatory factor 1; Short=BSF-1
- term:
id: GO:0010628
label: positive regulation of gene expression
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: IL-4 upregulates expression of numerous genes through STAT6 signaling,
including GATA3, AID, germline Ig epsilon transcripts, CD23, and MHC class II
molecules.
action: ACCEPT
reason: This is a broad but correct IEA annotation from ARBA. IL-4 is a potent
inducer of gene expression in immune cells. More specific transcription regulation
terms are also annotated.
supported_by:
- reference_id: PMID:12574355
supporting_text: IL-4 was able to induce AID expression in human primary B cells
and B cell lines
- term:
id: GO:0030335
label: positive regulation of cell migration
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: IL-4 can promote cell migration in certain contexts, including macrophage
and tumor cell migration. This is a secondary, context-dependent effect.
action: KEEP_AS_NON_CORE
reason: While there is evidence that IL-4 can regulate cell migration, this is
not a core function of the cytokine. It represents a pleiotropic downstream
effect rather than the primary evolved function. The ARBA-generated IEA annotation
is acceptable but should not be considered a defining function.
- term:
id: GO:0042113
label: B cell activation
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: IL-4 is a major B cell activating factor that induces B cell proliferation,
class switching to IgE and IgG, and upregulation of MHC class II and CD23. This
is one of the historically defining functions of IL-4 (originally named B-cell
stimulatory factor 1).
action: ACCEPT
reason: B cell activation is a core function of IL-4. The IEA from UniProt keyword
mapping accurately reflects that IL-4 was originally identified as BSF-1 precisely
because of its B cell activating properties.
supported_by:
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: Induces the expression of class II MHC molecules on resting
B-cells. Enhances both secretion and cell surface expression of IgE and IgG1
- term:
id: GO:0045321
label: leukocyte activation
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: IL-4 activates multiple leukocyte types including B cells, T cells, macrophages,
and dendritic cells. This is a broad parent term.
action: ACCEPT
reason: This broad IEA term is correct. IL-4 activates multiple leukocyte populations.
More specific child terms (B cell activation, T cell activation, macrophage
activation) are also annotated.
- term:
id: GO:0051239
label: regulation of multicellular organismal process
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: IL-4 regulates immune processes at the organismal level, affecting allergic
responses, anti-helminth immunity, and tissue remodeling.
action: MARK_AS_OVER_ANNOTATED
reason: This is an extremely broad and uninformative term. While technically true,
it provides no useful information about IL-4 function. More specific terms are
available and annotated. The ARBA machine learning annotation is too general
to be informative.
- term:
id: GO:0080090
label: regulation of primary metabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: IL-4 can regulate metabolic processes in target cells, but this is an
extremely broad and uninformative annotation.
action: MARK_AS_OVER_ANNOTATED
reason: This term is far too general to be informative for IL-4 annotation. While
IL-4 signaling does affect metabolic processes in target cells, this ARBA-generated
term does not convey any meaningful biological insight about the protein.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:10219247
review:
summary: PMID:10219247 reports the crystal structure of IL-4 in complex with IL4RA
at 2.30 angstroms resolution, demonstrating direct protein-protein interaction.
The WITH column specifies UniProtKB:P24394 (IL4R).
action: MODIFY
reason: The protein binding annotation is uninformative. The interaction demonstrated
in PMID:10219247 is specifically IL-4 binding to the IL-4 receptor alpha chain,
which is better captured by GO:0005136 (interleukin-4 receptor binding), which
is already annotated via IEA, TAS, and IDA evidence.
proposed_replacement_terms:
- id: GO:0005136
label: interleukin-4 receptor binding
supported_by:
- reference_id: PMID:10219247
supporting_text: IL-4 binds with high affinity and specificity to the ectodomain
of the IL-4 receptor alpha chain (IL4-BP)
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 25-153 IN COMPLEX
WITH IL4R...INTERACTION WITH IL4R
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18243101
review:
summary: PMID:18243101 reports the crystal structure of IL-4 in complex with IL13RA1
and IL4RA, elucidating the molecular basis of cytokine receptor pleiotropy in
the IL-4/IL-13 system. The GOA TSV shows two separate annotations from this
PMID, one with IL4R (P24394) and one with IL13RA1 (P78552).
action: MODIFY
reason: The generic protein binding term is uninformative. The interaction with
IL4RA is better captured by GO:0005136, and the interaction with IL13RA1 represents
a component of the type II receptor complex formation.
proposed_replacement_terms:
- id: GO:0005136
label: interleukin-4 receptor binding
supported_by:
- reference_id: PMID:18243101
supporting_text: Here we present the crystal structures of the complete set
of type I (IL-4R alpha/gamma(c)/IL-4) and type II (IL-4R alpha/IL-13R alpha1/IL-4,
IL-4R alpha/IL-13R alpha1/IL-13) ternary signaling complexes
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: X-RAY CRYSTALLOGRAPHY (2.93 ANGSTROMS) OF 25-153...INTERACTION
WITH IL13RA1, AND FUNCTION
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23597562
review:
summary: PMID:23597562 is about a small-molecule FGFR inhibitor (SSR128129E) and
its anti-tumor angiogenesis effects. The WITH column specifies IL4R (P24394).
This annotation likely derives from an IntAct high-throughput dataset associated
with this publication where IL4-IL4R interaction was detected.
action: MODIFY
reason: The IL-4/IL-4R interaction is well-established but the generic protein
binding term is uninformative. If the interaction is genuine, it is better captured
by GO:0005136 (interleukin-4 receptor binding). Additionally, the primary publication
focus is FGFR biology, making the provenance of this specific annotation unclear.
proposed_replacement_terms:
- id: GO:0005136
label: interleukin-4 receptor binding
supported_by:
- reference_id: PMID:23597562
supporting_text: we report the pharmacologic characterization of the chemical
SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR)
signaling
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:8266078
review:
summary: PMID:8266078 demonstrates that the IL-2 receptor gamma chain is a functional
component of the IL-4 receptor, showing IL-4 binding and signaling through the
IL4RA/IL2RG complex.
action: MODIFY
reason: As with the other protein binding annotations for IL-4, the interaction
with IL4R is better captured by the specific term GO:0005136 (interleukin-4
receptor binding). The generic protein binding term is uninformative.
proposed_replacement_terms:
- id: GO:0005136
label: interleukin-4 receptor binding
supported_by:
- reference_id: PMID:8266078
supporting_text: IL-2R gamma was demonstrated to be a component of the IL-4
receptor on the basis of chemical cross-linking data, the ability of IL-2R
gamma to augment IL-4 binding affinity, and the requirement for IL-2R gamma
in IL-4-mediated phosphorylation of insulin receptor substrate-1
- term:
id: GO:0007259
label: cell surface receptor signaling pathway via JAK-STAT
evidence_type: IDA
original_reference_id: PMID:23103943
review:
summary: IL-4 signals through JAK1/JAK3 (type I receptor) and JAK1/TYK2 (type
II receptor) to activate STAT6, and to a lesser extent STAT3. This annotation
captures the canonical signaling mechanism.
action: ACCEPT
reason: JAK-STAT signaling is the primary intracellular signaling pathway activated
by IL-4. The IDA annotation from ComplexPortal is well-supported by extensive
literature.
supported_by:
- reference_id: PMID:23103943
supporting_text: Formation of the IL-4/IL-4Rα/γc or IL-4/IL-4Rα/IL-13Rα1 complex
on the cell surface activates intracellular signaling pathways including the
Jak-STAT and the PI3K/Akt pathways
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: Engagement of both types of receptors initiates JAK3 and to
a lower extend JAK1 phosphorylation leading to activation of the signal transducer
and activator of transcription 6/STAT6
- reference_id: file:human/IL4/IL4-deep-research-falcon.md
supporting_text: JAK-STAT is canonical...type I (primarily JAK1/JAK3) and type
II (JAK2/TYK2 reported), converging on STAT6
- term:
id: GO:0035771
label: interleukin-4-mediated signaling pathway
evidence_type: NAS
original_reference_id: PMID:18243101
review:
summary: PMID:18243101 elucidated the structural basis for cytokine receptor pleiotropy
in the IL-4/IL-13 system, providing mechanistic insight into IL-4 signaling
through both type I and type II receptor complexes.
action: ACCEPT
reason: This NAS annotation is well-supported. The referenced paper provides definitive
structural evidence for IL-4 receptor complex assembly, which is the initiating
event of the IL-4-mediated signaling pathway. Duplicate of the IBA annotation
but with different evidence, which is acceptable.
supported_by:
- reference_id: PMID:18243101
supporting_text: Here we present the crystal structures of the complete set
of type I (IL-4R alpha/gamma(c)/IL-4) and type II (IL-4R alpha/IL-13R alpha1/IL-4,
IL-4R alpha/IL-13R alpha1/IL-13) ternary signaling complexes
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: X-RAY CRYSTALLOGRAPHY...OF 25-153, DISULFIDE BONDS, INTERACTION
WITH IL13RA1, AND FUNCTION
- term:
id: GO:0042531
label: positive regulation of tyrosine phosphorylation of STAT protein
evidence_type: NAS
original_reference_id: PMID:18243101
review:
summary: IL-4 receptor engagement leads to JAK-mediated phosphorylation of STAT6
(at Y641) and STAT3 (at Y705). This is a direct mechanistic consequence of IL-4
signaling.
action: ACCEPT
reason: STAT6 tyrosine phosphorylation is the key signaling event downstream of
IL-4 receptor activation. The NAS annotation from ComplexPortal accurately captures
this core signaling mechanism. The Reactome pathway also documents JAK1 phosphorylation
of STAT3 and STAT6.
supported_by:
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: Engagement of both types of receptors initiates JAK3 and to
a lower extend JAK1 phosphorylation leading to activation of the signal transducer
and activator of transcription 6/STAT6
- reference_id: PMID:12574355
supporting_text: IL-4-dependent AID induction was inhibited by a dominant-negative
STAT6, indicating that IL-4 induced AID expression via the Janus kinase (JAK)/STAT6
signaling pathway
- term:
id: GO:1902107
label: positive regulation of leukocyte differentiation
evidence_type: NAS
original_reference_id: PMID:23103943
review:
summary: IL-4 drives differentiation of multiple leukocyte lineages including
Th2 cells from naive T cells, dendritic cells from monocytes, and M2 macrophages
from monocytes/ macrophages.
action: ACCEPT
reason: This is a well-supported annotation. IL-4 is a key driver of leukocyte
differentiation programs, particularly Th2 differentiation and dendritic cell
differentiation. The NAS evidence from ComplexPortal is consistent with extensive
experimental data.
supported_by:
- reference_id: PMID:23103943
supporting_text: Cytokines dimerize their receptors, with the binding of the
'second chain' triggering signaling
- reference_id: file:human/IL4/IL4-deep-research-falcon.md
supporting_text: IL-4 drives Th2 differentiation (via STAT6->GATA3), B-cell
proliferation and class-switch recombination to IgE, and alternative (M2)
macrophage activation
- term:
id: GO:0007259
label: cell surface receptor signaling pathway via JAK-STAT
evidence_type: IGI
original_reference_id: PMID:12574355
review:
summary: PMID:12574355 demonstrates that IL-4 induces AID expression via JAK/STAT6
signaling, and that CD45 negatively regulates this pathway by acting as a JAK
phosphatase. The IGI annotation with STAT6 (P42226) provides genetic interaction
evidence.
action: ACCEPT
reason: The paper directly demonstrates IL-4 activates JAK/STAT6 signaling using
dominant- negative STAT6 experiments. The genetic interaction with STAT6 provides
strong evidence for this pathway annotation.
supported_by:
- reference_id: PMID:12574355
supporting_text: IL-4-dependent AID induction was inhibited by a dominant-negative
STAT6, indicating that IL-4 induced AID expression via the Janus kinase (JAK)/STAT6
signaling pathway
- term:
id: GO:0035771
label: interleukin-4-mediated signaling pathway
evidence_type: IDA
original_reference_id: PMID:12574355
review:
summary: PMID:12574355 directly demonstrates IL-4 signaling through JAK/STAT6
in the context of AID gene induction in B cells.
action: ACCEPT
reason: The paper provides direct experimental evidence for IL-4-mediated signaling
pathway activation using IL-4 stimulation of B cells and demonstrating JAK-dependent
STAT6 activation.
supported_by:
- reference_id: PMID:12574355
supporting_text: IL-4 was able to induce AID expression in human primary B cells
and B cell lines...IL-4-induced AID expression was further enhanced by CD40
signaling
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IGI
original_reference_id: PMID:12574355
review:
summary: PMID:12574355 shows IL-4 induces AID gene transcription through STAT6-dependent
mechanisms. The IGI evidence includes interactions with CD45 (P08575), CD40
(P29965), and STAT6 (P42226).
action: ACCEPT
reason: The paper demonstrates IL-4 positively regulates transcription of the
AID gene in B cells, with genetic interaction evidence from STAT6 dominant-negative,
CD45, and CD40 experiments.
supported_by:
- reference_id: PMID:12574355
supporting_text: IL-4 was able to induce AID expression in human primary B cells
and B cell lines, and IL-4-induced AID expression was further enhanced by
CD40 signaling
- term:
id: GO:0005125
label: cytokine activity
evidence_type: IDA
original_reference_id: PMID:10219247
review:
summary: PMID:10219247 reports the crystal structure of the IL-4/IL4RA complex
and characterizes the receptor binding interface, providing direct structural
evidence for IL-4's cytokine activity.
action: ACCEPT
reason: This IDA annotation is well-supported. The referenced paper demonstrates
direct IL-4/receptor interaction through structural analysis, confirming IL-4
functions as a cytokine that binds and activates its cognate receptor.
supported_by:
- reference_id: PMID:10219247
supporting_text: Interleukin-4 (IL-4) is a principal regulatory cytokine during
an immune response and a crucial determinant for allergy and asthma
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: Crystal structure of the interleukin-4/receptor alpha chain
complex reveals a mosaic binding interface
- term:
id: GO:0005615
label: extracellular space
evidence_type: IDA
original_reference_id: PMID:3279117
review:
summary: PMID:3279117 demonstrates that exogenous recombinant IL-4 acts on monocytes
in culture, confirming its activity as a secreted extracellular protein. The
paper shows IL-4 modulates monocyte phenotype and function when added to culture
medium.
action: ACCEPT
reason: IL-4 is a secreted cytokine with a signal peptide. Its localization to
the extracellular space is unambiguous. The paper demonstrates IL-4 acting as
an extracellular factor on monocytes.
supported_by:
- reference_id: PMID:3279117
supporting_text: Highly purified peripheral blood monocytes were cultured in
the presence of rIL-4
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Secreted'
- term:
id: GO:0035771
label: interleukin-4-mediated signaling pathway
evidence_type: IDA
original_reference_id: PMID:10219247
review:
summary: PMID:10219247 provides structural evidence for IL-4 receptor complex
formation, the initiating event of the IL-4-mediated signaling pathway.
action: ACCEPT
reason: The crystal structure of IL-4 bound to IL4RA demonstrates the molecular
basis of IL-4 signaling initiation. This IDA annotation is well-supported and
consistent with other annotations for the same GO term.
supported_by:
- reference_id: PMID:10219247
supporting_text: this intermediate complex recruits the common gamma chain (gamma
c), thereby initiating transmembrane signaling
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: Crystal structure of the interleukin-4/receptor alpha chain
complex reveals a mosaic binding interface
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:11967989
review:
summary: PMID:11967989 shows that IL-4 attenuates TGF-beta-stimulated induction
of CTGF mRNA expression in human lung fibroblasts, through interference with
TGF-beta-induced transcriptional activation of the CTGF gene.
action: KEEP_AS_NON_CORE
reason: The paper demonstrates IL-4 can negatively regulate specific gene transcription
(CTGF), but this is a context-specific effect in lung fibroblasts rather than
a core function of IL-4. IL-4's primary role is transcriptional activation of
immune genes, not transcriptional repression.
supported_by:
- reference_id: PMID:11967989
supporting_text: IL-4 attenuated the TGF-beta-stimulated induction of CTGF mRNA
expression by 50%...IL-4 interfered with the TGF-beta-induced transcriptional
activation of the CTGF gene
- term:
id: GO:1903845
label: negative regulation of cellular response to transforming growth factor
beta stimulus
evidence_type: IDA
original_reference_id: PMID:11967989
review:
summary: PMID:11967989 directly demonstrates that IL-4 antagonizes TGF-beta signaling
in lung fibroblasts by attenuating TGF-beta-induced CTGF expression.
action: KEEP_AS_NON_CORE
reason: While the paper provides direct evidence for this annotation, IL-4's antagonism
of TGF-beta signaling in fibroblasts is a tissue-specific context-dependent
effect, not a core function of the cytokine. This represents pleiotropic activity.
supported_by:
- reference_id: PMID:11967989
supporting_text: IL-4 attenuated the TGF-beta-stimulated induction of CTGF mRNA
expression by 50%. This effect was selective because IL-4 did not affect fibronectin
or alpha1(I) collagen mRNA expression induced by TGF-beta
- term:
id: GO:0008284
label: positive regulation of cell population proliferation
evidence_type: IGI
original_reference_id: PMID:31432141
review:
summary: PMID:31432141 identifies IL-4 as a direct target of miR-320a in trophoblast
cells (HTR-8/SVneo). Rescue experiments demonstrate that IL-4 overexpression
partially reverses the anti-proliferative effect of miR-320a on trophoblast
cells (MTT assay). The IGI evidence involves miR-320a (RNAcentral:URS00003CF1AD_9606)
with acts_upstream_of_or_within qualifier. The proliferation effect is in trophoblast
cells in the context of preeclampsia.
action: KEEP_AS_NON_CORE
reason: The paper provides evidence that IL-4 promotes trophoblast cell proliferation
in the preeclampsia context. While IL-4 also promotes B and T cell proliferation
as a core function (annotated separately via ISS), this specific annotation
reflects a non-immune cell proliferation effect that is not a core function
of the cytokine.
supported_by:
- reference_id: PMID:31432141
supporting_text: restoring the expression level of IL-4 partially decreased
the inhibitory effect of miR-320a overexpression on HTR-8/SVneo cell proliferation
- reference_id: PMID:31432141
supporting_text: Collectively, the present data suggested that IL-4 was a functional
target gene of miR-320a, and miR-320a upregulation inhibited the proliferation
and invasion of HTR-8/SVneo cells by directly targeting IL-4
- term:
id: GO:0030335
label: positive regulation of cell migration
evidence_type: IGI
original_reference_id: PMID:31432141
review:
summary: PMID:31432141 studies miR-320a in preeclampsia trophoblast cells (HTR-8/SVneo).
IL-4 is identified as a direct target of miR-320a. Rescue experiments show that
overexpression of IL-4 partially reverses the inhibitory effect of miR-320a
on trophoblast cell invasion (Transwell assay). The IGI evidence involves miR-320a
(RNAcentral:URS00003CF1AD_9606) as the interacting partner, with acts_upstream_of_or_within
qualifier. The cell migration/invasion effect is in trophoblast cells, not immune
cells.
action: KEEP_AS_NON_CORE
reason: The paper provides evidence that IL-4 promotes trophoblast cell invasion
in the context of preeclampsia, which is consistent with the IEA annotation
for the same term that was already marked KEEP_AS_NON_CORE. Cell migration promotion
is not a core immune function of IL-4 but represents a pleiotropic effect in
non-immune cell types.
supported_by:
- reference_id: PMID:31432141
supporting_text: overexpression of IL-4 in HTR-8/SVneo cells reduced the inhibitory
effect of miR-320a overexpression on cell invasion
- reference_id: PMID:31432141
supporting_text: miR-320a upregulation inhibited the proliferation and invasion
of HTR-8/SVneo cells by directly targeting IL-4
- term:
id: GO:0032733
label: positive regulation of interleukin-10 production
evidence_type: IGI
original_reference_id: PMID:30634164
review:
summary: PMID:30634164 studies macrophage polarization and shows that M2 macrophages
(induced by IL-4 and IL-13) express higher levels of IL-10 than M1 macrophages.
The IGI evidence involves IL-13 (P35225), reflecting the cooperative use of
IL-4 and IL-13 in M2 polarization protocols.
action: ACCEPT
reason: The paper demonstrates that IL-4/IL-13-induced M2 macrophages express
higher IL-10 levels than M1 macrophages, supporting IL-4's role in promoting
IL-10 production. This is consistent with IL-4's well-established anti-inflammatory
M2-polarizing function and the known IL-10 production by M2 macrophages.
supported_by:
- reference_id: PMID:30634164
supporting_text: M1 macrophages express higher levels of IL-16 than M2 macrophages
but express lower levels of IL-10 and mir-145 than M2 cells
- term:
id: GO:0042116
label: macrophage activation
evidence_type: IGI
original_reference_id: PMID:30634164
review:
summary: PMID:30634164 uses IL-4 and IL-13 to induce M2 macrophage polarization
from THP-1 monocytes. IL-4 is a canonical driver of alternative macrophage activation
(M2 polarization). The IGI evidence with IL-13 (P35225) reflects the cooperative
use of these cytokines in M2 polarization.
action: ACCEPT
reason: M2 macrophage activation by IL-4 is one of its best-established functions.
The paper directly uses IL-4 in the M2 polarization protocol. This is extensively
documented in the deep research and is a core function of IL-4 in innate immunity.
supported_by:
- reference_id: PMID:30634164
supporting_text: THP-1 cells were induced by IL-4 and IL-13 following PMA incubation
(M2 polarized macrophages) or induced by IFN-gamma and LPS (M1 classical macrophage
activation)
- reference_id: file:human/IL4/IL4-deep-research-falcon.md
supporting_text: IL-4 drives...alternative (M2) macrophage activation; IL-13
overlaps but acts more directly on structural cells
- term:
id: GO:0050728
label: negative regulation of inflammatory response
evidence_type: IGI
original_reference_id: PMID:30634164
review:
summary: PMID:30634164 demonstrates that IL-4/IL-13-induced M2 macrophages have
an anti-inflammatory profile with high IL-10 and low pro-inflammatory cytokines.
IL-4 suppresses inflammatory responses through M2 macrophage polarization. The
IGI evidence with IL-13 (P35225) reflects cooperative anti-inflammatory signaling.
action: ACCEPT
reason: This is a duplicate of the IBA annotation for the same term, with independent
IGI evidence. The anti-inflammatory role of IL-4 is well-established and represents
a core function. Duplicate annotations with different evidence codes are acceptable.
supported_by:
- reference_id: PMID:30634164
supporting_text: THP-1 cells were induced by IL-4 and IL-13 following PMA incubation
(M2 polarized macrophages) or induced by IFN-gamma and LPS (M1 classical macrophage
activation)
- reference_id: file:human/IL4/IL4-deep-research-falcon.md
supporting_text: IL-4 drives...alternative (M2) macrophage activation
- term:
id: GO:0010628
label: positive regulation of gene expression
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: IL-4 upregulates gene expression in target cells through STAT6-mediated
transcriptional activation. Transferred from mouse IL-4 (P07750) and rat IL-4
(P20096).
action: ACCEPT
reason: This ISS annotation is well-supported by the conserved function of IL-4
across mammals. IL-4 is a potent inducer of gene expression through STAT6 signaling.
The annotation is consistent with the IDA evidence for transcription regulation
and with the IEA annotation for the same term.
supported_by:
- reference_id: PMID:12574355
supporting_text: IL-4 was able to induce AID expression in human primary B cells
and B cell lines
- term:
id: GO:0150076
label: neuroinflammatory response
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: IL-4 has been implicated in neuroinflammation, particularly in the context
of neuroprotection and microglial polarization. Transferred from mouse IL-4
(P20096) by ARUK-UCL curators.
action: KEEP_AS_NON_CORE
reason: While IL-4 has documented roles in neuroinflammation (primarily anti-inflammatory/
neuroprotective effects via M2 microglial polarization), this is a tissue-specific
context-dependent activity, not a core immune function of IL-4. The ISS from
mouse is reasonable but this represents a specialized function.
- term:
id: GO:0032720
label: negative regulation of tumor necrosis factor production
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: IL-4 suppresses TNF-alpha production, particularly in macrophages, as
part of its anti-inflammatory and M2-polarizing activity. Transferred from mouse
IL-4 (P07750).
action: ACCEPT
reason: Suppression of TNF-alpha production is a well-established function of
IL-4 in the context of its anti-inflammatory M2 macrophage polarization program.
The ISS from mouse is appropriate given conserved IL-4 function.
supported_by:
- reference_id: file:human/IL4/IL4-deep-research-falcon.md
supporting_text: IL-4 drives...alternative (M2) macrophage activation
- term:
id: GO:1901857
label: positive regulation of cellular respiration
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: IL-4 has been reported to promote mitochondrial respiration in macrophages
as part of M2 metabolic reprogramming. Transferred from mouse IL-4 (P07750)
by ARUK-UCL.
action: KEEP_AS_NON_CORE
reason: While IL-4-driven M2 macrophage polarization involves metabolic reprogramming
toward oxidative phosphorylation, this metabolic effect is a downstream consequence
of M2 polarization rather than a core function of IL-4 itself. The annotation
is not incorrect but represents a specialized downstream effect.
- term:
id: GO:2001171
label: positive regulation of ATP biosynthetic process
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Related to the metabolic reprogramming of M2 macrophages toward oxidative
phosphorylation. Transferred from mouse IL-4 (P07750) by ARUK-UCL.
action: KEEP_AS_NON_CORE
reason: This is a highly specific metabolic effect that is downstream of M2 macrophage
polarization. Not a core function of IL-4 as a cytokine. Over-specific annotation
of a downstream metabolic consequence.
- term:
id: GO:0150079
label: negative regulation of neuroinflammatory response
evidence_type: IC
original_reference_id: GO_REF:0000111
review:
summary: IC annotation inferred from ISS evidence. IL-4 has anti-inflammatory
effects in the CNS, promoting M2 microglial polarization and suppressing neuroinflammation.
action: KEEP_AS_NON_CORE
reason: While IL-4 has documented neuroprotective and anti-neuroinflammatory effects,
these are tissue-specific activities rather than core immune functions. The
IC evidence based on ISS is reasonable but this represents a specialized function.
- term:
id: GO:0048260
label: positive regulation of receptor-mediated endocytosis
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: IL-4 may promote receptor-mediated endocytosis in certain cell types,
possibly related to amyloid-beta clearance by microglia. Transferred from mouse
IL-4 (P07750 and P20096) by ARUK-UCL.
action: KEEP_AS_NON_CORE
reason: This annotation likely relates to IL-4's role in promoting microglial
phagocytic clearance of amyloid-beta, which is a very specialized neuroimmune
function rather than a core IL-4 activity.
- term:
id: GO:1900223
label: positive regulation of amyloid-beta clearance
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: IL-4 has been reported to promote amyloid-beta clearance by microglia
in Alzheimer's disease models. Transferred from mouse IL-4 (P07750 and P20096)
by ARUK-UCL.
action: KEEP_AS_NON_CORE
reason: While there is mouse literature supporting IL-4's role in promoting amyloid-beta
clearance, this is a highly specialized neuroimmune function that is far from
the core evolved function of IL-4 as an immune cytokine. The ISS transfer is
reasonable but this represents a tissue-specific activity.
- term:
id: GO:0016239
label: positive regulation of macroautophagy
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: IL-4 has been reported to stimulate autophagy in dendritic cells. The
UniProt function annotation notes IL-4 stimulates autophagy by interfering with
mTORC1 signaling and through RUFY4 induction. Transferred from mouse IL-4 (P07750).
action: KEEP_AS_NON_CORE
reason: While UniProt documents this function, autophagy induction is a specialized
downstream effect of IL-4 signaling rather than a core function. The ISS annotation
is supported by the UniProt function description.
supported_by:
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: Stimulates autophagy in dendritic cells by interfering with
mTORC1 signaling and through the induction of RUFY4
- term:
id: GO:0120162
label: positive regulation of cold-induced thermogenesis
evidence_type: ISS
original_reference_id: PMID:24906148
review:
summary: PMID:24906148 demonstrates that IL-4/IL-13 signaling in macrophages is
required for cold-induced beige fat biogenesis. Administration of IL-4 to thermoneutral
mice increases beige fat mass and thermogenic capacity. The ISS is from mouse
IL-4 (P07750).
action: KEEP_AS_NON_CORE
reason: While the paper provides compelling evidence that IL-4 promotes beige
fat thermogenesis through alternatively activated macrophages, this is a specialized
metabolic function far removed from IL-4's core immune role.
supported_by:
- reference_id: PMID:24906148
supporting_text: Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced
biogenesis of beige fat
- reference_id: PMID:24906148
supporting_text: administration of IL-4 to thermoneutral mice increases beige
fat mass and thermogenic capacity to ameliorate pre-established obesity
- term:
id: GO:0042110
label: T cell activation
evidence_type: IGI
original_reference_id: PMID:18337562
review:
summary: PMID:18337562 is about CCL5-mediated T cell chemotaxis involving mTOR/4E-BP1
translation initiation. The paper studied CD4+ T cell migration in response
to CCL5, not IL-4. The IGI evidence involves CD82 (P10747). The connection to
IL-4 is unclear.
action: UNDECIDED
reason: The referenced publication (PMID:18337562) is about CCL5 (RANTES)-mediated
T cell chemotaxis, not IL-4 function. While IL-4 is known to activate T cells
(particularly driving Th2 differentiation), this specific annotation appears
to reference an unrelated paper. The annotation may have been made based on
a secondary finding or data in the paper, but the primary focus is CCL5.
supported_by:
- reference_id: PMID:18337562
supporting_text: CCL5-mediated T-cell chemotaxis involves the initiation of
mRNA translation through mTOR/4E-BP1
- term:
id: GO:0045892
label: negative regulation of DNA-templated transcription
evidence_type: IDA
original_reference_id: PMID:16606666
review:
summary: PMID:16606666 demonstrates that IL-4 inhibits B7-H4 (VTCN1) expression
on tumor macrophages in human ovarian carcinoma. IL-4 negatively regulates B7-H4
transcription, in contrast to IL-6 and IL-10 which stimulate its expression.
action: KEEP_AS_NON_CORE
reason: The paper provides direct evidence that IL-4 negatively regulates B7-H4
expression on macrophages. This is consistent with the other GO:0045892 annotation
from PMID:18579517 (also KEEP_AS_NON_CORE) and the GO:0000122 annotation from
PMID:11967989 for CTGF. IL-4's ability to repress specific genes is a real but
context-dependent activity, not a core function.
supported_by:
- reference_id: PMID:16606666
supporting_text: granulocyte/macrophage colony-stimulating factor and IL-4,
which are limited in the tumor microenvironment, inhibit B7-H4 expression
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6785821
review:
summary: Reactome annotation for IL-4 participation in the IL-4/IL-13 signaling
pathway, specifically the SOCS5/SOCS1 binding to IL4RA reaction. IL-4 is correctly
placed in the extracellular region.
action: ACCEPT
reason: IL-4 is a secreted cytokine in the extracellular region. These Reactome
TAS annotations correctly reflect IL-4's participation in signaling pathway
reactions as an extracellular ligand.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6786058
review:
summary: Reactome annotation for IL-4 signaling - JAK1 binding to IL4R in IL4-bound
complex.
action: ACCEPT
reason: Duplicate CC annotation from Reactome pathway. IL-4 is correctly localized
to the extracellular region as part of the receptor-ligand complex.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6786070
review:
summary: Reactome annotation for type II receptor complex assembly (IL-4 complex
binding IL13RA1/TYK2).
action: ACCEPT
reason: Duplicate CC annotation from Reactome pathway. Correct localization.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6786072
review:
summary: Reactome annotation for STAT3/STAT6 dissociation step in IL-4 signaling.
action: ACCEPT
reason: Duplicate CC annotation from Reactome pathway. Correct localization.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6786092
review:
summary: Reactome annotation for type I receptor complex assembly (IL-4 complex
binding IL2RG/JAK3).
action: ACCEPT
reason: Duplicate CC annotation from Reactome pathway. Correct localization.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6786095
review:
summary: Reactome annotation for JAK1 phosphorylation of STAT3/STAT6 in IL-4 signaling.
action: ACCEPT
reason: Duplicate CC annotation from Reactome pathway. Correct localization.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6786096
review:
summary: Reactome annotation for phosphorylation of IL4R/IL2RG/JAK1 components.
action: ACCEPT
reason: Duplicate CC annotation from Reactome pathway. Correct localization.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6786101
review:
summary: Reactome annotation for IL-4 binding to IL4R/JAK2.
action: ACCEPT
reason: Duplicate CC annotation from Reactome pathway. Correct localization.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6786124
review:
summary: Reactome annotation for STAT3/STAT6 binding to phosphorylated IL4R.
action: ACCEPT
reason: Duplicate CC annotation from Reactome pathway. Correct localization.
- term:
id: GO:0043011
label: myeloid dendritic cell differentiation
evidence_type: IDA
original_reference_id: PMID:16116184
review:
summary: PMID:16116184 studies galectin-9 effects on monocyte-derived dendritic
cells that were generated using the standard IL-4 + GM-CSF protocol. The paper
uses IL-4 to differentiate monocytes into immature DCs, which are then matured
by galectin-9.
action: ACCEPT
reason: IL-4 is a well-established driver of dendritic cell differentiation from
monocytes. The paper directly employs IL-4 in the DC differentiation protocol.
The IL-4 + GM-CSF system for DC generation is one of the most widely used in
immunology.
supported_by:
- reference_id: PMID:16116184
supporting_text: Gal-9 had no or little effect on differentiation of human monocytes
into immature DCs
- term:
id: GO:1903660
label: negative regulation of complement-dependent cytotoxicity
evidence_type: IMP
original_reference_id: PMID:16034134
review:
summary: PMID:16034134 demonstrates that IL-4 and IL-13 induce protection of porcine
endothelial cells from killing by human complement through PI3K/Akt signaling.
action: KEEP_AS_NON_CORE
reason: The paper provides direct evidence that IL-4 protects endothelial cells
from complement-mediated killing via PI3K/Akt pathway activation. This is a
specialized cytoprotective effect in the xenotransplantation context, not a
core immune function of IL-4.
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
review:
summary: PMID:16034134 demonstrates that IL-4 protects porcine endothelial cells
from apoptosis induced by TNF-alpha plus cycloheximide through PI3K/Akt signaling.
action: KEEP_AS_NON_CORE
reason: The paper provides direct evidence that IL-4 protects endothelial cells
from apoptosis via PI3K/Akt pathway activation. This represents a cytoprotective
effect consistent with IL-4's known anti-apoptotic signaling but in a non-immune
cell context.
supported_by:
- reference_id: PMID:16034134
supporting_text: IL-4 and IL-13 can induce protection of porcine EC against
killing by apoptosis and human complement through activation of the PI3K/Akt
signaling pathway
- term:
id: GO:0010633
label: negative regulation of epithelial cell migration
evidence_type: IDA
original_reference_id: PMID:11698262
review:
summary: PMID:11698262 demonstrates that IL-4 and IL-13 decrease wound healing
and migration in Calu-3 human lung epithelial cells. IL-4 treatment decreased
cell migration in wound-healing assays on collagen I.
action: KEEP_AS_NON_CORE
reason: The paper provides direct evidence that IL-4 inhibits epithelial cell
migration in lung epithelial cells. This is a tissue-specific effect on non-immune
cells in the context of airway epithelial barrier function and wound healing,
representing a pleiotropic activity rather than a core immune function.
supported_by:
- reference_id: PMID:11698262
supporting_text: In wound-healing assays of cells grown on collagen I, IL-4
and IL-13 decreased migration, whereas IFN-gamma treatment enhanced migration,
compared with control cells
- term:
id: GO:0097028
label: dendritic cell differentiation
evidence_type: IDA
original_reference_id: PMID:21149635
review:
summary: PMID:21149635 demonstrates that monocytic cells derived from human embryonic
stem cells differentiate through pathways involving IL-4, with M2-like macrophage
characteristics.
action: ACCEPT
reason: IL-4 is well-established as a key factor in dendritic cell differentiation
from monocyte precursors. The paper studies monocyte differentiation pathways
including IL-4 dependent steps. This is consistent with the GO:0043011 annotation.
supported_by:
- reference_id: PMID:21149635
supporting_text: monocytic cells derived from human embryonic stem cells (hESCs)
and from fetal liver follow a differentiation pathway different to that of
adult cells
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: IDA
original_reference_id: PMID:19346497
review:
summary: PMID:19346497 studies IFN-lambda1 inhibition of GATA3 and Th2 responses.
The paper demonstrates IL-4-driven transcription in the context of Th2 cytokine
gene expression. IL-4 stimulation leads to GATA3 expression and IL-4Ralpha upregulation,
both of which are transcription-dependent processes.
action: ACCEPT
reason: IL-4 is a potent inducer of gene transcription through STAT6 signaling.
This IDA annotation is consistent with multiple other annotations for the same
term and with the known biology of IL-4.
supported_by:
- reference_id: PMID:19346497
supporting_text: Expression of Th2 cytokines (IL-4 and IL-13) was suppressed
in naive and memory CD4(+) T cells by IFN-lambda1, without affecting their
proliferation
- term:
id: GO:0032736
label: positive regulation of interleukin-13 production
evidence_type: IDA
original_reference_id: PMID:19346497
review:
summary: PMID:19346497 demonstrates that IL-4-driven Th2 responses include IL-13
production, which is suppressed by IFN-lambda1. The paper shows IL-4 promotes
IL-13 expression as part of the Th2 cytokine program.
action: ACCEPT
reason: IL-4 and IL-13 are co-regulated Th2 cytokines. IL-4-driven Th2 differentiation
via GATA3 leads to increased IL-13 production as part of the Th2 cytokine program.
The paper directly demonstrates this relationship.
supported_by:
- reference_id: PMID:19346497
supporting_text: Expression of Th2 cytokines (IL-4 and IL-13) was suppressed
in naive and memory CD4(+) T cells by IFN-lambda1, without affecting their
proliferation
- reference_id: file:human/IL4/IL4-deep-research-falcon.md
supporting_text: IL-4 drives Th2 differentiation (via STAT6->GATA3)
- term:
id: GO:0045582
label: positive regulation of T cell differentiation
evidence_type: IDA
original_reference_id: PMID:20554961
review:
summary: PMID:20554961 studies IL-4-driven Th2 differentiation and how type I
IFN opposes it. IL-4 promotes Th2 development by inducing GATA3.
action: ACCEPT
reason: IL-4 is the canonical driver of Th2 cell differentiation from naive T
cells. The paper directly studies this process and demonstrates IL-4-dependent
GATA3 induction as the key mechanism of Th2 commitment.
supported_by:
- reference_id: PMID:20554961
supporting_text: IL-4 promotes Th2 development by inducing the expression of
the GATA3 transcription factor, and the Th2 phenotype is stabilized by a GATA3-dependent
auto-regulatory loop
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: IDA
original_reference_id: PMID:20554961
review:
summary: PMID:20554961 demonstrates that IL-4 promotes transcription of GATA3
through STAT6 signaling as part of Th2 commitment.
action: ACCEPT
reason: The paper provides direct evidence that IL-4 activates GATA3 transcription
through STAT6, consistent with the known transcription-activating function of
IL-4.
supported_by:
- reference_id: PMID:20554961
supporting_text: IL-4 receptor signaling promotes STAT6 recruitment and phosphorylation...
which ultimately regulates induction of GATA3 transcription
- term:
id: GO:2000553
label: positive regulation of T-helper 2 cell cytokine production
evidence_type: IDA
original_reference_id: PMID:20554961
review:
summary: PMID:20554961 demonstrates that IL-4 promotes Th2 cytokine production
by driving GATA3-dependent Th2 differentiation and cytokine gene expression.
action: ACCEPT
reason: IL-4-driven Th2 differentiation leads to increased production of Th2 cytokines
(IL-4, IL-5, IL-13). This is a core function of IL-4 as the master Th2-polarizing
cytokine.
supported_by:
- reference_id: PMID:20554961
supporting_text: IL-4 promotes Th2 development by inducing the expression of
the GATA3 transcription factor
- term:
id: GO:0045892
label: negative regulation of DNA-templated transcription
evidence_type: IDA
original_reference_id: PMID:18579517
review:
summary: PMID:18579517 demonstrates that IL-4 stimulation negatively regulates
expression of LEF-1 and TCF-1 transcription factors in primary T cells, creating
a positive feedback loop that reinforces IL-4 gene expression by removing transcriptional
repressors. This represents IL-4 negatively regulating transcription of specific
target genes (LEF-1, TCF-1).
action: KEEP_AS_NON_CORE
reason: The paper provides direct evidence that IL-4 downregulates LEF-1 and TCF-1
expression, which are Wnt pathway transcription factors. This is consistent
with the existing KEEP_AS_NON_CORE annotation for GO:0000122 (negative regulation
of transcription by RNA polymerase II) from PMID:11967989 for CTGF. IL-4's ability
to repress specific genes is a real but secondary function compared to its primary
role as a transcriptional activator through STAT6.
supported_by:
- reference_id: PMID:18579517
supporting_text: we found that IL-4 stimulation possesses a negative effect
on the expressions of LEF-1 and TCF-1 in primary T cells, suggesting a positive
feedback effect of IL-4 on IL4 gene expression
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: IDA
original_reference_id: PMID:18579517
review:
summary: PMID:18579517 demonstrates that IL-4 positively regulates its own gene
expression through a feedback mechanism. IL-4 stimulation suppresses LEF-1 and
TCF-1, which are negative regulators of the IL-4 promoter. Knockdown of LEF-1
by siRNA increased IL-4 mRNA expression, confirming that LEF-1 is a transcriptional
repressor of IL-4. By removing this repression, IL-4 indirectly promotes transcription
of IL-4 and potentially other Th2 cytokine genes.
action: ACCEPT
reason: The paper provides evidence that IL-4 positively regulates transcription
through a feedback loop involving suppression of LEF-1/TCF-1 transcriptional
repressors. This is consistent with the other ACCEPT annotations for GO:0045893
from IBA, IDA (PMID:19346497, PMID:20554961), which all document IL-4's well-established
role as a transcriptional activator via STAT6 signaling.
supported_by:
- reference_id: PMID:18579517
supporting_text: Knockdown LEF-1 expression by LEF-1-specific small interfering
RNA resulted in an increase in the IL-4 mRNA expression
- reference_id: PMID:18579517
supporting_text: we found that IL-4 stimulation possesses a negative effect
on the expressions of LEF-1 and TCF-1 in primary T cells, suggesting a positive
feedback effect of IL-4 on IL4 gene expression
- term:
id: GO:0008203
label: cholesterol metabolic process
evidence_type: ISS
original_reference_id: PMID:11971948
review:
summary: PMID:11971948 demonstrates that IL-4-deficient mice have a 100% incidence
of gallstones and cholesterol crystals on a fat-enriched diet, compared to no
gallstones in wild-type mice, suggesting IL-4 plays a role in cholesterol metabolism.
ISS from mouse IL-4 (P07750).
action: KEEP_AS_NON_CORE
reason: The paper provides genetic evidence that IL-4 deficiency predisposes to
gallstone formation and altered cholesterol metabolism. However, this is a pleiotropic
downstream effect rather than a core immune function of IL-4.
supported_by:
- reference_id: PMID:11971948
supporting_text: IL-4(-/-) mice had a 100% incidence of gallstones and cholesterol
crystals
- term:
id: GO:0030890
label: positive regulation of B cell proliferation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: IL-4 promotes B cell proliferation as one of its defining functions.
Originally named B-cell stimulatory factor 1 (BSF-1) for this activity. Transferred
from mouse IL-4 (P07750).
action: ACCEPT
reason: B cell proliferation is a core function of IL-4. It was originally identified
as BSF-1 precisely for its B cell growth-promoting activity. The ISS from mouse
is well-supported by extensive human data.
supported_by:
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: AltName...B-cell stimulatory factor 1; Short=BSF-1
- term:
id: GO:0042102
label: positive regulation of T cell proliferation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: IL-4 promotes T cell proliferation, particularly of Th2-committed cells.
Also known as lymphocyte stimulatory factor 1. Transferred from mouse IL-4 (P07750).
action: ACCEPT
reason: T cell proliferation promotion is a known function of IL-4, consistent
with its alternative name as lymphocyte stimulatory factor 1. The ISS from mouse
is well-supported.
supported_by:
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: AltName...Lymphocyte stimulatory factor 1
- term:
id: GO:0043066
label: negative regulation of apoptotic process
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: IL-4 has well-documented anti-apoptotic effects, promoting survival of
B cells, T cells, and other immune cells through PI3K/Akt signaling. Transferred
from mouse IL-4 (P07750).
action: KEEP_AS_NON_CORE
reason: While IL-4 has anti-apoptotic effects through IRS-2/PI3K signaling, this
is a secondary consequence of its signaling rather than a core function. The
annotation is not incorrect but represents a downstream effect.
- term:
id: GO:0045348
label: positive regulation of MHC class II biosynthetic process
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: IL-4 induces MHC class II expression on B cells, enhancing their antigen-presenting
capacity. This is one of IL-4's original defining functions. Transferred from
mouse IL-4 (P07750).
action: ACCEPT
reason: MHC class II upregulation on B cells by IL-4 is one of the earliest described
functions of this cytokine and is directly documented in the UniProt function
annotation. The ISS from mouse is well-supported by human data.
supported_by:
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: Induces the expression of class II MHC molecules on resting
B-cells
- term:
id: GO:0045671
label: negative regulation of osteoclast differentiation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: IL-4 has been reported to inhibit osteoclast differentiation, likely
through anti-inflammatory effects that oppose RANKL signaling. Transferred from
mouse IL-4 (P07750).
action: KEEP_AS_NON_CORE
reason: While IL-4 may inhibit osteoclastogenesis, this is a specialized tissue-specific
effect rather than a core immune function. The ISS annotation is from mouse
data and represents a pleiotropic activity.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: IL-4 activates RNA polymerase II-dependent transcription through STAT6-mediated
signaling. Transferred from mouse IL-4 (P07750).
action: ACCEPT
reason: This is well-supported by the IGI annotation with the same term from PMID:12574355
and by the known mechanism of STAT6-dependent gene activation. The ISS from
mouse is consistent with human data.
- term:
id: GO:0048295
label: positive regulation of isotype switching to IgE isotypes
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: IL-4 is the primary cytokine that drives B cell class switch recombination
to IgE. This is arguably the most important and specific function of IL-4 in
adaptive immunity, and the basis for anti-IL-4 therapy in allergic disease.
Transferred from mouse IL-4 (P07750).
action: ACCEPT
reason: IgE class switching is THE defining function of IL-4 in B cell biology.
IL-4 induces germline epsilon transcription through STAT6 signaling, which is
required for IgE class switch recombination. This is the mechanistic basis for
dupilumab therapy in allergic diseases.
supported_by:
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: Enhances both secretion and cell surface expression of IgE
and IgG1
- reference_id: file:human/IL4/IL4-deep-research-falcon.md
supporting_text: IL-4 drives...B-cell proliferation and class-switch recombination
to IgE
- term:
id: GO:0048304
label: positive regulation of isotype switching to IgG isotypes
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: IL-4 promotes IgG1 (in mouse) and IgG4 (in human) class switching. Transferred
from mouse IL-4 (P07750).
action: ACCEPT
reason: IL-4 promotes IgG class switching in addition to IgE switching. In humans,
IL-4 drives switching to IgG4; in mice, to IgG1. This is a well-established
function.
supported_by:
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: Enhances both secretion and cell surface expression of IgE
and IgG1
- term:
id: GO:0050776
label: regulation of immune response
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: IL-4 regulates immune responses, particularly type 2 immunity. Transferred
from mouse IL-4 (P07750). Duplicate of the IBA annotation.
action: ACCEPT
reason: Duplicate of the IBA annotation with ISS evidence. Both are correct and
complementary.
- term:
id: GO:0005136
label: interleukin-4 receptor binding
evidence_type: TAS
original_reference_id: PMID:3016727
review:
summary: PMID:3016727 is the original paper by Yokota et al. (1986) reporting
the cloning and characterization of human IL-4 cDNA, including its B-cell and
T-cell stimulating activities through receptor binding.
action: ACCEPT
reason: This is the seminal paper identifying human IL-4. The TAS annotation for
IL-4 receptor binding from the original characterization paper is historically
and scientifically well-supported.
supported_by:
- reference_id: PMID:3016727
supporting_text: Supernatant of COS-7 monkey cells transfected with the human
cDNA clone stimulated proliferation of human helper T-cell clones and of anti-IgM-activated
human B cells, two properties of mouse BSF-1 on mouse cells
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION...Isolation
and characterization of a human interleukin cDNA clone, homologous to mouse
B-cell stimulatory factor 1
- term:
id: GO:0005615
label: extracellular space
evidence_type: TAS
original_reference_id: PMID:3016727
review:
summary: The original IL-4 cloning paper by Yokota et al. (1986) characterizes
IL-4 as a secreted protein with a putative signal peptide and extracellular
activity.
action: ACCEPT
reason: Correct localization annotation from the original characterization paper.
supported_by:
- reference_id: PMID:3016727
supporting_text: The human cDNA contains a single open reading frame encoding
a protein of 153 amino acid residues including a putative signal peptide
- term:
id: GO:0006955
label: immune response
evidence_type: TAS
original_reference_id: PMID:3016727
review:
summary: IL-4 was characterized as an immune response cytokine in the original
cloning paper, showing B-cell and T-cell stimulating activities.
action: ACCEPT
reason: IL-4 is fundamentally an immune response mediator. The TAS annotation
from the original characterization paper is correct.
supported_by:
- reference_id: PMID:3016727
supporting_text: Supernatant of COS-7 monkey cells transfected with the human
cDNA clone stimulated proliferation of human helper T-cell clones and of anti-IgM-activated
human B cells
- term:
id: GO:0005136
label: interleukin-4 receptor binding
evidence_type: TAS
original_reference_id: PMID:11418631
review:
summary: PMID:11418631 studies IL-4 receptor-mediated signaling in the context
of germinal center B cell differentiation, demonstrating that IL-4 acts through
its receptor to direct GC-B cell fate toward memory B cells.
action: ACCEPT
reason: IL-4 receptor binding is the core molecular function. The paper demonstrates
IL-4 receptor-mediated biological effects. Duplicate with different reference
is acceptable.
supported_by:
- reference_id: PMID:11418631
supporting_text: IL-4 directs GC-B cells to differentiate into memory B cells,
whereas IL-10 steers them into PC
- term:
id: GO:0005615
label: extracellular space
evidence_type: TAS
original_reference_id: PMID:11418631
review:
summary: PMID:11418631 studies the effects of T cell-derived cytokines including
secreted IL-4 on germinal center B cell differentiation, consistent with IL-4
activity in the extracellular space.
action: ACCEPT
reason: Correct localization. IL-4 is a secreted cytokine that acts in the extracellular
space. Duplicate with different reference is acceptable.
supported_by:
- reference_id: PMID:11418631
supporting_text: cytokines secreted by activated T cells determined the pathway
of GC-B cell differentiation
- term:
id: GO:0008083
label: growth factor activity
evidence_type: NAS
original_reference_id: PMID:11418631
review:
summary: PMID:11418631 demonstrates that IL-4 and FDC signals provide growth-promoting
signals for germinal center B cells. IL-4 has growth factor activity for B and
T cells (originally named BSF-1).
action: KEEP_AS_NON_CORE
reason: While IL-4 has growth-promoting activity for lymphocytes, its primary
molecular function is better described as cytokine activity and IL-4 receptor
binding. Growth factor activity is a secondary characterization.
supported_by:
- reference_id: PMID:11418631
supporting_text: FDC/HK cells do not direct either pathway, but provide signals
for proliferation of GC-B cells
- term:
id: GO:0030183
label: B cell differentiation
evidence_type: TAS
original_reference_id: PMID:11418631
review:
summary: PMID:11418631 directly demonstrates that IL-4 directs germinal center
B cells to differentiate into memory B cells, while IL-10 steers them toward
plasma cells.
action: ACCEPT
reason: B cell differentiation is a core function of IL-4. The paper provides
direct evidence for IL-4's role in directing GC-B cell differentiation pathways.
supported_by:
- reference_id: PMID:11418631
supporting_text: IL-4 directs GC-B cells to differentiate into memory B cells,
whereas IL-10 steers them into PC
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: Enhances both secretion and cell surface expression of IgE
and IgG1
- term:
id: GO:0042092
label: type 2 immune response
evidence_type: TAS
original_reference_id: PMID:11676128
review:
summary: PMID:11676128 reviews IL-4, IL-5, and IL-13 as Th2 cytokines pivotal
in regulating the allergic phenotype, IgE response, and inflammatory cell-mediated
function. IL-4 is THE defining cytokine of type 2 immune responses.
action: ACCEPT
reason: Type 2 immune response is the most accurate high-level description of
IL-4's biological role. IL-4 is the master regulator of type 2 immunity.
supported_by:
- reference_id: PMID:11676128
supporting_text: Th2 cytokines, such as IL-4, IL-5 and IL-13, are pivotal in
regulating the allergic phenotype, the IgE response or the inflammatory cell-mediated
function
- reference_id: file:human/IL4/IL4-deep-research-falcon.md
supporting_text: IL-4 is a central driver of type-2 endotypes (eosinophilic/allergic)
across airway and barrier diseases
- term:
id: GO:0045191
label: regulation of isotype switching
evidence_type: TAS
original_reference_id: PMID:11418631
review:
summary: PMID:11418631 studies the role of T cell-derived cytokines including
IL-4 in germinal center B cell differentiation, which includes isotype switching.
IL-4 is the primary cytokine regulating class switch recombination to IgE and
IgG4 in humans.
action: ACCEPT
reason: Isotype switching regulation is a core function of IL-4. More specific
child terms (IgE and IgG switching) are also annotated. This general term appropriately
captures the broader regulatory role.
supported_by:
- reference_id: PMID:11418631
supporting_text: IL-4 directs GC-B cells to differentiate into memory B cells,
whereas IL-10 steers them into PC
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: Enhances both secretion and cell surface expression of IgE
and IgG1
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO
terms
findings: []
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
by curator judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
findings: []
- id: GO_REF:0000111
title: Gene Ontology annotations Inferred by Curator (IC) using at least one Inferred
by Sequence Similarity (ISS) annotation to support the inference
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning models
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:3016727
title: Isolation and characterization of a human interleukin cDNA clone, homologous
to mouse B-cell stimulatory factor 1, that expresses B-cell- and T-cell-stimulating
activities
findings:
- statement: Original cloning and characterization of human IL-4 as a secreted cytokine
with B cell and T cell stimulating activities.
supporting_text: Supernatant of COS-7 monkey cells transfected with the human
cDNA clone stimulated proliferation of human helper T-cell clones and of anti-IgM-activated
human B cells, two properties of mouse BSF-1 on mouse cells
- id: PMID:10219247
title: Crystal structure of the interleukin-4/receptor alpha chain complex reveals
a mosaic binding interface
findings:
- statement: Crystal structure at 2.30 angstroms reveals the IL-4/IL4RA binding
interface and demonstrates direct ligand-receptor interaction.
supporting_text: The crystal structure of the intermediate complex between human
IL-4 and IL4-BP was determined at 2.3 A resolution. It reveals a novel spatial
orientation of the two proteins, a small but unexpected conformational change
in the receptor-bound IL-4, and an interface with three separate clusters of
trans-interacting residues
- id: PMID:11418631
title: The distinct roles of T cell-derived cytokines and a novel follicular dendritic
cell-signaling molecule 8D6 in germinal center-B cell differentiation.
findings:
- statement: Characterization of IL-4 receptor binding, growth factor activity,
and role in B cell differentiation and isotype switching.
supporting_text: IL-4 directs GC-B cells to differentiate into memory B cells,
whereas IL-10 steers them into PC
- id: PMID:11676128
title: '[Inflammatory cytokines (IL-4, IL-5 and IL-13)].'
findings:
- statement: Documents IL-4 role in type 2 immune responses.
supporting_text: Th2 cytokines, such as IL-4, IL-5 and IL-13, are pivotal in regulating
the allergic phenotype, the IgE response or the inflammatory cell-mediated function
- id: PMID:11698262
title: Lung epithelial barrier function and wound healing are decreased by IL-4
and IL-13 and enhanced by IFN-gamma.
findings:
- statement: IL-4 and IL-13 decrease lung epithelial barrier function and wound
healing, inhibiting epithelial cell migration on collagen substrates.
supporting_text: In wound-healing assays of cells grown on collagen I, IL-4 and
IL-13 decreased migration, whereas IFN-gamma treatment enhanced migration, compared
with control cells
- id: PMID:11967989
title: Interleukin-4 regulates connective tissue growth factor expression in human
lung fibroblasts.
findings:
- statement: IL-4 attenuates TGF-beta-stimulated CTGF expression in lung fibroblasts
by interfering with TGF-beta-induced transcriptional activation of the CTGF
gene.
supporting_text: IL-4 attenuated the TGF-beta-stimulated induction of CTGF mRNA
expression by 50%. This effect was selective because IL-4 did not affect fibronectin
or alpha1(I) collagen mRNA expression induced by TGF-beta
- id: PMID:11971948
title: Interleukin-4 deficiency promotes gallstone formation.
findings:
- statement: IL-4 deficiency in mice promotes gallstone formation on a fat-enriched
diet, suggesting a role for IL-4 in cholesterol metabolism.
supporting_text: IL-4(-/-) mice had a 100% incidence of gallstones and cholesterol
crystals
- id: PMID:12574355
title: 'Human activation-induced cytidine deaminase is induced by IL-4 and negatively
regulated by CD45: implication of CD45 as a Janus kinase phosphatase in antibody
diversification'
findings:
- statement: IL-4 induces AID expression in human B cells via JAK/STAT6 signaling,
enhanced by CD40 co-stimulation, and negatively regulated by CD45 JAK phosphatase
activity.
supporting_text: IL-4 was able to induce AID expression in human primary B cells
and B cell lines, and IL-4-induced AID expression was further enhanced by CD40
signaling. IL-4-dependent AID induction was inhibited by a dominant-negative
STAT6, indicating that IL-4 induced AID expression via the Janus kinase (JAK)/STAT6
signaling pathway
- 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-4 and IL-13 protect porcine endothelial cells from complement-mediated
killing and apoptosis via PI3K/Akt pathway activation.
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
- id: PMID:16116184
title: Galectin-9 induces maturation of human monocyte-derived dendritic cells.
findings:
- statement: IL-4 drives myeloid dendritic cell differentiation from monocyte precursors.
supporting_text: Culture of immature DCs with exogenous Gal-9 markedly increased
the surface expression of CD40, CD54, CD80, CD83, CD86, and HLA-DR in a dose-dependent
manner, although Gal-9 had no or little effect on differentiation of human monocytes
into immature DCs
- id: PMID:16606666
title: B7-H4 expression identifies a novel suppressive macrophage population in
human ovarian carcinoma.
findings:
- statement: IL-4 inhibits B7-H4 expression on macrophages, in contrast to IL-6
and IL-10 which stimulate it, relevant to tumor immune evasion.
supporting_text: granulocyte/macrophage colony-stimulating factor and IL-4, which
are limited in the tumor microenvironment, inhibit B7-H4 expression
- id: PMID:18243101
title: Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13
system
findings:
- statement: Crystal structure reveals molecular basis for IL-4 signaling through
both type I (IL4RA/IL2RG) and type II (IL4RA/IL13RA1) receptor complexes, explaining
cytokine receptor pleiotropy.
supporting_text: Here we present the crystal structures of the complete set of
type I (IL-4R alpha/gamma(c)/IL-4) and type II (IL-4R alpha/IL-13R alpha1/IL-4,
IL-4R alpha/IL-13R alpha1/IL-13) ternary signaling complexes
- id: PMID:18337562
title: CCL5-mediated T-cell chemotaxis involves the initiation of mRNA translation
through mTOR/4E-BP1.
findings:
- statement: Study of CCL5-mediated T cell chemotaxis mechanisms; relevance to IL-4
T cell activation annotation is unclear.
supporting_text: The multistep, coordinated process of T-cell chemotaxis requires
chemokines, and their chemokine receptors, to invoke signaling events to direct
cell migration
- id: PMID:18579517
title: LEF-1 negatively controls interleukin-4 expression through a proximal promoter
regulatory element.
findings:
- statement: LEF-1 is a transcriptional repressor of IL-4 gene expression. IL-4
stimulation downregulates LEF-1 and TCF-1, creating a positive feedback loop
that reinforces IL-4 expression.
supporting_text: Knockdown LEF-1 expression by LEF-1-specific small interfering
RNA resulted in an increase in the IL-4 mRNA expression
- id: PMID:19346497
title: IFN-lambda1 (IL-29) inhibits GATA3 expression and suppresses Th2 responses
in human naive and memory T cells.
findings:
- statement: IFN-lambda1 suppresses IL-4-driven Th2 responses by inhibiting GATA3
expression and Th2 cytokine (IL-4, IL-13) production in naive and memory T cells.
supporting_text: Expression of Th2 cytokines (IL-4 and IL-13) was suppressed in
naive and memory CD4(+) T cells by IFN-lambda1, without affecting their proliferation
- id: PMID:20554961
title: 'Cutting edge: Type I IFN reverses human Th2 commitment and stability by
suppressing GATA3'
findings:
- statement: IL-4 promotes Th2 development by inducing GATA3 expression via STAT6;
GATA3 autoregulation maintains Th2 stability; type I IFN can reverse this.
supporting_text: IL-4 promotes Th2 development by inducing the expression of the
GATA3 transcription factor, and the Th2 phenotype is stabilized by a GATA3-dependent
autoregulatory loop
- id: PMID:21149635
title: Monocytic cells derived from human embryonic stem cells and fetal liver share
common differentiation pathways and homeostatic functions
findings:
- statement: Demonstrates IL-4-dependent monocyte-to-dendritic cell differentiation
pathways in human embryonic and fetal systems.
supporting_text: monocytic cells derived from human embryonic stem cells (hESCs)
and from fetal liver follow a differentiation pathway different to that of adult
cells, leading to specific functions
- id: PMID:23103943
title: Redirecting cell-type specific cytokine responses with engineered interleukin-4
superkines.
findings:
- statement: Documents IL-4 signaling through JAK-STAT pathway and leukocyte differentiation.
supporting_text: Formation of the IL-4/IL-4Rα/γc or IL-4/IL-4Rα/IL-13Rα1 complex
on the cell surface activates intracellular signaling pathways including the
Jak-STAT and the PI3K/Akt pathways
- id: PMID:23597562
title: Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF
receptor blocker with allosteric properties
findings:
- statement: Study focuses on FGFR inhibitors; IL-4/IL4R interaction likely from
high-throughput IntAct data associated with this publication.
supporting_text: we report the pharmacologic characterization of the chemical
SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling
by binding to the extracellular FGFR domain without affecting orthosteric FGF
binding
- id: PMID:24906148
title: Eosinophils and type 2 cytokine signaling in macrophages orchestrate development
of functional beige fat.
findings:
- statement: IL-4/IL-13 signaling in macrophages is required for cold-induced beige
fat biogenesis. IL-4 administration increases beige fat and ameliorates obesity.
supporting_text: Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced
biogenesis of beige fat
- id: PMID:30634164
title: IL-16 regulates macrophage polarization as a target gene of mir-145-3p.
findings:
- statement: IL-4 and IL-13 induce M2 macrophage polarization with higher IL-10
and lower pro-inflammatory cytokine expression compared to M1 macrophages.
supporting_text: THP-1 cells were induced by IL-4 and IL-13 following PMA incubation
(M2 polarized macrophages) or induced by IFN-gamma and LPS (M1 classical macrophage
activation)
- id: PMID:31432141
title: miR‑320a upregulation contributes to the development of preeclampsia by inhibiting
the growth and invasion of trophoblast cells by targeting interleukin 4.
findings:
- statement: IL-4 is a direct target of miR-320a in trophoblast cells. IL-4 promotes
trophoblast proliferation and invasion, and miR-320a-mediated IL-4 suppression
contributes to preeclampsia pathogenesis.
supporting_text: miR-320a upregulation inhibited the proliferation and invasion
of HTR-8/SVneo cells by directly targeting IL-4
- id: PMID:3279117
title: Modulation of phenotypic and functional properties of human peripheral blood
monocytes by IL-4.
findings:
- statement: IL-4 modulates monocyte phenotype and function, inducing macrophage-like
morphology, MHC class II upregulation, and inhibiting secretion of cytostatic
and chemotactic compounds.
supporting_text: Highly purified peripheral blood monocytes were cultured in the
presence of rIL-4
- id: PMID:8266078
title: 'Interleukin-2 receptor gamma chain: a functional component of the interleukin-4
receptor.'
findings:
- statement: The IL-2 receptor gamma chain is a functional component of the IL-4
receptor, demonstrated by chemical cross-linking, binding affinity augmentation,
and requirement for IL-4-mediated IRS-1 phosphorylation.
supporting_text: IL-2R gamma was demonstrated to be a component of the IL-4 receptor
on the basis of chemical cross-linking data, the ability of IL-2R gamma to augment
IL-4 binding affinity, and the requirement for IL-2R gamma in IL-4-mediated
phosphorylation of insulin receptor substrate-1
- id: Reactome:R-HSA-6785821
title: SOCS5,(SOCS1) bind IL4RA
findings: []
- id: Reactome:R-HSA-6786058
title: JAK1 binds IL4R in IL4-bound IL4R1
findings: []
- id: Reactome:R-HSA-6786070
title: IL4:IL4R:JAK2 binds IL13RA1:TYK2
findings: []
- id: Reactome:R-HSA-6786072
title: p-Y705-STAT3,p-Y641-STAT6 dissociate
findings: []
- id: Reactome:R-HSA-6786092
title: IL4:IL4R:JAK2 binds IL2RG:JAK3
findings: []
- id: Reactome:R-HSA-6786095
title: JAK1 phosphorylates STAT3,STAT6
findings: []
- id: Reactome:R-HSA-6786096
title: IL4R, IL2RG, JAK1 in IL4-bound IL4R1:JAK1 are phosphorylated
findings: []
- id: Reactome:R-HSA-6786101
title: IL4 binds IL4R:JAK2
findings: []
- id: Reactome:R-HSA-6786124
title: STAT3,STAT6 bind p-Y-IL4R
findings: []
core_functions:
- description: IL-4 binds the IL-4 receptor alpha chain (IL4RA) to initiate type I
(IL4RA/IL2RG) and type II (IL4RA/IL13RA1) receptor complex assembly, driving JAK1/JAK3-STAT6
signaling that promotes Th2 differentiation, IgE class switching, and type 2 immune
responses
supported_by:
- reference_id: PMID:10219247
supporting_text: Crystal structure of the interleukin-4/receptor alpha chain complex
reveals a mosaic binding interface
- reference_id: PMID:12574355
supporting_text: IL-4 induced AID expression via the Janus kinase (JAK)/STAT6
signaling pathway
- reference_id: file:human/IL4/IL4-deep-research-falcon.md
supporting_text: IL-4 is a central driver of type-2 endotypes
molecular_function:
id: GO:0005136
label: interleukin-4 receptor binding
directly_involved_in:
- id: GO:0035771
label: interleukin-4-mediated signaling pathway
- id: GO:0042092
label: type 2 immune response
- id: GO:0048295
label: positive regulation of isotype switching to IgE isotypes
locations:
- id: GO:0005576
label: extracellular region
- description: IL-4 drives naive CD4+ T cell differentiation into Th2 effector cells
through STAT6-dependent GATA3 induction, promoting type 2 adaptive immunity
supported_by:
- reference_id: PMID:20554961
supporting_text: IL-4 promotes Th2 development by inducing the expression of the
GATA3 transcription factor
molecular_function:
id: GO:0005136
label: interleukin-4 receptor binding
directly_involved_in:
- id: GO:0045582
label: positive regulation of T cell differentiation
- id: GO:0045893
label: positive regulation of DNA-templated transcription
locations:
- id: GO:0005576
label: extracellular region
- description: IL-4 promotes B cell activation, proliferation, and class switch recombination
to IgE and IgG4, through induction of AID expression via STAT6
supported_by:
- reference_id: PMID:12574355
supporting_text: IL-4 was able to induce AID expression in human primary B cells
and B cell lines, and IL-4-induced AID expression was further enhanced by CD40
signaling
- reference_id: file:human/IL4/IL4-uniprot.txt
supporting_text: Enhances both secretion and cell surface expression of IgE and
IgG1
molecular_function:
id: GO:0005136
label: interleukin-4 receptor binding
directly_involved_in:
- id: GO:0042113
label: B cell activation
- id: GO:0048295
label: positive regulation of isotype switching to IgE isotypes
locations:
- id: GO:0005576
label: extracellular region
- description: IL-4 suppresses pro-inflammatory responses by inhibiting Th1 differentiation
and macrophage pro-inflammatory cytokine production, promoting M2 macrophage polarization
supported_by:
- reference_id: file:human/IL4/IL4-deep-research-falcon.md
supporting_text: IL-4 is a central driver of type-2 endotypes (eosinophilic/allergic)
across airway and barrier diseases
molecular_function:
id: GO:0005136
label: interleukin-4 receptor binding
directly_involved_in:
- id: GO:0050728
label: negative regulation of inflammatory response
- id: GO:0042116
label: macrophage activation
locations:
- id: GO:0005576
label: extracellular region