Interleukin-22 (IL-22) is a secreted cytokine of the IL-10 family that plays critical roles in innate immunity, tissue repair, and inflammation at barrier surfaces. Unlike most cytokines, IL-22 acts primarily on non-immune cells (epithelial cells, hepatocytes) through the IL-22R1/IL-10RB receptor complex, activating JAK-STAT signaling to promote antimicrobial defense, epithelial proliferation, and tissue regeneration. IL-22 is produced mainly by activated T cells (Th17/Th22) and innate lymphoid cells (ILC3) in response to infection and inflammation. Its activity is tightly regulated by the soluble antagonist IL-22BP (IL-22RA2), creating a balanced system essential for maintaining barrier integrity while preventing excessive tissue responses.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005125 cytokine activity | IBA GO_REF:0000033 | ACCEPT | Summary: Cytokine activity is a well-established core molecular function of IL-22. Multiple lines of evidence confirm IL-22 functions as a secreted signaling molecule that binds to cell surface receptors (IL-22R1/IL-10RB) to mediate intercellular communication. The IBA annotation is based on phylogenetic inference from well-characterized orthologs across vertebrates. Reason: IL-22 is definitively a cytokine - it is a secreted protein that signals through specific receptors to mediate immune and tissue responses. This is supported by extensive structural, biochemical, and functional studies since its discovery in 2000. The protein binds IL-22R1 with high affinity and signals through JAK-STAT pathways, fulfilling all criteria for cytokine activity. Supporting Evidence: PMID:10875937 We report the identification of a novel human cytokine, distantly related to interleukin (IL)-10, which we term IL-22. IL-22 is produced by activated T cells. IL-22 is a ligand for CRF2-4, a member of the class II cytokine receptor family. PMID:10954742 IL-10-related T cell-derived inducible factor (IL-TIF or IL-21) is a new cytokine structurally related to IL-10 and originally identified in the mouse as a gene induced by IL-9 in T cells and mast cells. |
| GO:0005615 extracellular space | IBA GO_REF:0000033 | ACCEPT | Summary: Core localization annotation. IL-22 is a secreted cytokine with an N-terminal signal peptide (aa 1-33) that is released into the extracellular space. Reason: IL-22 is synthesized as a 179-amino-acid precursor with a 33-residue signal peptide and secreted into the extracellular space where it acts on target cells. Supporting Evidence: file:human/IL22/IL22-uniprot.txt CC -!- SUBCELLULAR LOCATION: Secreted. file:human/IL22/IL22-deep-research.md IL-22 is a secreted protein. It contains an N-terminal signal peptide (amino acids 1β33) that directs it into the endoplasmic reticulum/Golgi secretory pathway, after which the mature cytokine is released into the extracellular space. |
| GO:0050728 negative regulation of inflammatory response | IBA GO_REF:0000033 | MODIFY | Summary: IL-22 has complex, context-dependent effects on inflammation. While it can have anti-inflammatory effects through tissue protection and barrier maintenance, it also has well-documented pro-inflammatory activities in many contexts, particularly in autoimmune diseases like psoriasis and rheumatoid arthritis. The negative regulation annotation captures only one aspect of IL-22 function. Reason: IL-22 has dual pro- and anti-inflammatory effects depending on context. In acute injury, it promotes tissue repair and can limit inflammation through barrier protection. However, in chronic inflammation (psoriasis, IBD), IL-22 often drives pathogenic inflammation. A more accurate annotation would be "regulation of inflammatory response" (GO:0050727) or maintaining both positive and negative regulation terms to capture this duality. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: REGULATORY SIGN INVERSION CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN009232695 Β· IL22 ancestral node SUPPORTS SOURCE BUT NOT TARGET IL-22 has context-dependent pro- and anti-inflammatory effects rather than strictly negative regulation. Proposed replacements: regulation of inflammatory response positive regulation of response to external stimulus Supporting Evidence: PMID:10875937 In contrast to IL-10, IL-22 does not inhibit the production of proinflammatory cytokines by monocytes in response to LPS nor does it impact IL-10 function on monocytes file:human/IL22/IL22-deep-research.md Importantly, IL-22βs effects are context-dependent: in an environment with ongoing infection or tissue stress, IL-22 is generally beneficial (enhancing antimicrobial immunity and repair), but in an already inflamed tissue without active infection, continual IL-22 signaling may contribute to **pathogenic inflammation**. |
| GO:0007165 signal transduction | IEA GO_REF:0000108 | MODIFY | Summary: Signal transduction is too general a term for IL-22. IL-22 specifically initiates the interleukin-22-mediated signaling pathway (GO:0140865) through the heterodimeric IL-22RA1/IL-10RB receptor complex. Reason: Refine the broad signal transduction term (GO:0007165) to its specific is_a descendant pathway term GO:0140865 (interleukin-22-mediated signaling pathway, an is_a child of GO:0019221 cytokine-mediated signaling pathway under GO:0007166 cell surface receptor signaling pathway). Proposed replacements: interleukin-22-mediated signaling pathway Supporting Evidence: PMID:10875937 Cell lines were identified that respond to IL-22 by activation of STATs 1, 3, and 5 PMID:10954742 Recombinant human IL-TIF was found to activate signal transducer and activator of transcription factors-1 and -3 in several hepatoma cell lines. |
| GO:0005125 cytokine activity | IEA GO_REF:0000043 | ACCEPT | Summary: Duplicate annotation of cytokine activity via automated keyword mapping. While correct, this duplicates the IBA annotation above which is based on stronger phylogenetic evidence. Reason: This is a correct annotation - IL-22 is definitively a cytokine. The IEA evidence is based on UniProt keyword mapping which correctly identifies IL-22 as a cytokine. Having multiple evidence codes for the same core function is acceptable and provides complementary support. Supporting Evidence: file:human/IL22/IL22-uniprot.txt CC -!- FUNCTION: Cytokine that plays a critical role in modulating tissue CC responses during inflammation (PubMed:17204547). |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: Core localization annotation. IL-22 functions in the extracellular region as a secreted cytokine. Reason: IL-22 is correctly annotated to the extracellular region. As a secreted cytokine, it functions outside cells in the extracellular environment where it binds cell-surface IL-22RA1/IL-10RB receptors or soluble IL-22RA2. Supporting Evidence: file:human/IL22/IL22-deep-research.md Consequently, the functional location of IL-22 is the extracellular region, where it diffuses to interact with receptors on target cell surfaces. |
| GO:0005615 extracellular space | IEA GO_REF:0000120 | ACCEPT | Summary: Core localization annotation. IL-22 is a secreted cytokine localized to the extracellular space. Reason: Electronic annotation from UniProt subcellular location (Secreted) correctly places IL-22 in the extracellular space. Supporting Evidence: file:human/IL22/IL22-uniprot.txt CC -!- SUBCELLULAR LOCATION: Secreted. |
| GO:0005515 protein binding | IPI PMID:12513909 Comparison of interleukin-22 and interleukin-10 soluble rece... | REMOVE | Summary: Generic protein binding annotation that provides minimal functional information; IL-22's receptor interaction is captured by cytokine activity (GO:0005125). Reason: Bare GO:0005515 (protein binding) is removed per repository policy; IL-22's interaction with its receptor complex (IL-22RA1/IL-10RB) and soluble decoy receptor (IL-22RA2) is represented by its core molecular function GO:0005125 (cytokine activity). Supporting Evidence: PMID:12513909 Comparison of interleukin-22 and interleukin-10 soluble receptor complexes |
| GO:0005515 protein binding | IPI PMID:18599299 Structure of IL-22 bound to its high-affinity IL-22R1 chain. | REMOVE | Summary: Generic protein binding annotation from structural study of the IL-22/IL-22R1 complex; covered by cytokine activity (GO:0005125). Reason: Bare GO:0005515 (protein binding) is removed per repository policy; the specific receptor-engaging activity of IL-22 is represented by GO:0005125 (cytokine activity). Supporting Evidence: PMID:18599299 Structure of IL-22 bound to its high-affinity IL-22R1 chain |
| GO:0005515 protein binding | IPI PMID:18675809 Crystal structure of the IL-22/IL-22R1 complex and its impli... | REMOVE | Summary: Generic protein binding annotation from IL-22/IL-22R1 structural study; covered by cytokine activity (GO:0005125). Reason: Bare GO:0005515 (protein binding) is removed per repository policy; the specific receptor-engaging activity of IL-22 is represented by GO:0005125 (cytokine activity). Supporting Evidence: PMID:18675809 Crystal structure of the IL-22/IL-22R1 complex and its implications for the IL-22 signaling mechanism |
| GO:0005515 protein binding | IPI PMID:20462497 Structure and mechanism of receptor sharing by the IL-10R2 c... | REMOVE | Summary: Generic protein binding annotation describing IL-10RB interaction; covered by cytokine activity (GO:0005125). Reason: Bare GO:0005515 (protein binding) is removed per repository policy; IL-22's engagement of the IL-22RA1/IL-10RB receptor complex is represented by GO:0005125 (cytokine activity). Supporting Evidence: PMID:20462497 Structure and mechanism of receptor sharing by the IL-10R2 common chain |
| GO:0051384 response to glucocorticoid | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Automated annotation suggesting IL-22 expression responds to glucocorticoids. While IL-22 production can be modulated by glucocorticoids in immune cells, this is not a core function of the IL-22 protein itself. Reason: IL-22 expression can be regulated by glucocorticoids as part of anti-inflammatory responses, but this represents regulation of IL-22 production rather than a core function of the IL-22 protein. This is a secondary/regulatory aspect rather than a defining characteristic of IL-22. Supporting Evidence: file:human/IL22/IL22-deep-research.md Conversely, anti-inflammatory cytokines like IL-10 or regulatory T cells can suppress IL-22 production. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-448480 | ACCEPT | Summary: Correct annotation from Reactome pathway showing IL-22 binding to IL-22RA1:JAK1 receptor complex in the extracellular space. Multiple Reactome annotations provide pathway-specific evidence. Reason: IL-22 functions in the extracellular region where it binds to its receptor complex. This Reactome annotation is based on curated pathway knowledge and is correct. Supporting Evidence: Reactome:R-HSA-448480 IL22 binds IL22RA1:JAK1 receptor complex [occurs in extracellular region] |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-448741 | ACCEPT | Summary: Correct annotation showing IL-22 binding to its soluble antagonist IL-22RA2 (IL-22BP) in the extracellular region. Reason: IL-22 is correctly localized to the extracellular region where it can be bound and neutralized by IL-22BP. This regulatory interaction occurs in the extracellular space. Supporting Evidence: PMID:11481447 We demonstrate that IL-22RA2 binds specifically to IL-22 and neutralizes IL-22-induced proliferation |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8854645 | ACCEPT | Summary: Another correct Reactome annotation showing IL-22 receptor complex formation in the extracellular region. Reason: Correctly shows IL-22 in the extracellular region as part of receptor complex assembly with IL-10RB:TYK2. Multiple Reactome pathways provide consistent evidence for extracellular localization. Supporting Evidence: Reactome:R-HSA-8854645 IL22:IL22RA1:JAK1 binds IL10RB:TYK2 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8986995 | ACCEPT | Summary: Correct Reactome annotation documenting IL-22 signaling pathway events in the extracellular region. Reason: IL-22 is correctly localized to the extracellular region in this Reactome pathway. Multiple independent Reactome pathways consistently place IL-22 in the extracellular space where it interacts with its receptors. Supporting Evidence: file:human/IL22/IL22-deep-research.md Consistent with this, Reactome and other pathway databases localize IL-22 to the extracellular region in human pathways. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8987014 | ACCEPT | Summary: Correct Reactome annotation documenting IL-22 signaling pathway events in the extracellular region. Reason: IL-22 is correctly localized to the extracellular region in this Reactome pathway. Multiple independent Reactome pathways consistently place IL-22 in the extracellular space where it interacts with its receptors. Supporting Evidence: file:human/IL22/IL22-deep-research.md Consistent with this, Reactome and other pathway databases localize IL-22 to the extracellular region in human pathways. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8987042 | ACCEPT | Summary: Correct Reactome annotation documenting IL-22 signaling pathway events in the extracellular region. Reason: IL-22 is correctly localized to the extracellular region in this Reactome pathway. Multiple independent Reactome pathways consistently place IL-22 in the extracellular space where it interacts with its receptors. Supporting Evidence: file:human/IL22/IL22-deep-research.md Consistent with this, Reactome and other pathway databases localize IL-22 to the extracellular region in human pathways. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8987070 | ACCEPT | Summary: Correct Reactome annotation documenting IL-22 signaling pathway events in the extracellular region. Reason: IL-22 is correctly localized to the extracellular region in this Reactome pathway. Multiple independent Reactome pathways consistently place IL-22 in the extracellular space where it interacts with its receptors. Supporting Evidence: file:human/IL22/IL22-deep-research.md Consistent with this, Reactome and other pathway databases localize IL-22 to the extracellular region in human pathways. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8987132 | ACCEPT | Summary: Correct Reactome annotation documenting IL-22 signaling pathway events in the extracellular region. Reason: IL-22 is correctly localized to the extracellular region in this Reactome pathway. Multiple independent Reactome pathways consistently place IL-22 in the extracellular space where it interacts with its receptors. Supporting Evidence: file:human/IL22/IL22-deep-research.md Consistent with this, Reactome and other pathway databases localize IL-22 to the extracellular region in human pathways. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8987236 | ACCEPT | Summary: Correct Reactome annotation documenting IL-22 signaling pathway events in the extracellular region. Reason: IL-22 is correctly localized to the extracellular region in this Reactome pathway. Multiple independent Reactome pathways consistently place IL-22 in the extracellular space where it interacts with its receptors. Supporting Evidence: file:human/IL22/IL22-deep-research.md Consistent with this, Reactome and other pathway databases localize IL-22 to the extracellular region in human pathways. |
| GO:0006953 acute-phase response | NAS PMID:11481447 A soluble class II cytokine receptor, IL-22RA2, is a natural... | ACCEPT | Summary: IL-22 induces acute-phase response in hepatocytes, a well-documented function. IL-22 stimulates production of acute phase proteins like serum amyloid A, haptoglobin, and alpha-1-antichymotrypsin in liver cells. Reason: Induction of acute-phase response is a core biological function of IL-22. Multiple studies demonstrate IL-22 activates STAT3 in hepatocytes to induce acute phase reactants. This is one of the originally discovered functions of IL-22 and remains a key aspect of its role in inflammation and innate immunity. Supporting Evidence: PMID:10954742 IL-TIF stimulation of HepG2 human hepatoma cells up-regulated the production of acute phase reactants such as serum amyloid A, alpha1-antichymotrypsin, and haptoglobin. PMID:11481447 Because IL-22 induces the expression of acute phase reactants, IL-22RA2 may play an important role as an IL-22 antagonist in the regulation of inflammatory responses. |
| GO:0006954 inflammatory response | NAS PMID:10954742 Human interleukin-10-related T cell-derived inducible factor... | ACCEPT | Summary: IL-22 participates in inflammatory responses, though its effects are complex and context-dependent. IL-22 can promote inflammation in autoimmune diseases but also has tissue-protective anti-inflammatory effects. Reason: IL-22 is involved in inflammatory response, though its role is nuanced. It contributes to inflammation through acute phase protein induction and tissue responses, but also promotes tissue repair. This broad annotation captures IL-22s involvement in inflammatory processes. Supporting Evidence: PMID:10954742 IL-TIF expression was found to be rapidly increased after lipopolysaccharide (LPS) injection, suggesting that this cytokine contributes to the inflammatory response in vivo. file:human/IL22/IL22-deep-research.md Importantly, IL-22βs effects are context-dependent: in an environment with ongoing infection or tissue stress, IL-22 is generally beneficial (enhancing antimicrobial immunity and repair), but in an already inflamed tissue without active infection, continual IL-22 signaling may contribute to **pathogenic inflammation**. |
| GO:0045518 interleukin-22 receptor binding | NAS PMID:10875937 Interleukin (IL)-22, a novel human cytokine that signals thr... | MODIFY | Summary: IL-22 binds the heterodimeric IL-22RA1/IL-10RB receptor complex to initiate JAK1/TYK2-STAT3 signaling. Under the signaling ligand curation convention, modify passive receptor-binding to the active signaling molecular function GO:0005125 (cytokine activity). Reason: Per the signaling ligand curation convention, receptor-binding terms on secreted cytokines are modified to GO:0005125 (cytokine activity) so that the active receptor-activating molecular function is asserted on the ligand rather than passive binding. Proposed replacements: cytokine activity Supporting Evidence: PMID:10875937 IL-22 is a ligand for CRF2-4, a member of the class II cytokine receptor family... A new member of the interferon receptor family, which we term IL-22R, functions as a second component together with CRF2-4 to enable IL-22 signaling. file:human/IL22/IL22-deep-research.md IL-22 binds to a heterodimeric receptor complex composed of IL-22RA1 (a cell-type specific Ξ±-chain on epithelial and stromal cells) and the shared IL-10RB (IL-10R2) Ξ²-chain. |
| GO:0007259 cell surface receptor signaling pathway via JAK-STAT | IDA PMID:10875937 Interleukin (IL)-22, a novel human cytokine that signals thr... | NEW | Summary: IL-22 signals through the heterodimeric IL-22RA1/IL-10RB receptor complex to activate JAK1/TYK2 and STAT3 (as well as STAT1 and STAT5). Reason: In GO, GO:0140865 (interleukin-22-mediated signaling pathway, is_a GO:0019221 cytokine-mediated signaling pathway) and GO:0007259 (cell surface receptor signaling pathway via JAK-STAT) are parallel branches under GO:0007166 (cell surface receptor signaling pathway); asserting both captures the ligand-specific pathway and the intracellular JAK-STAT signaling mechanism, parallel to human IL21. Supporting Evidence: PMID:10875937 Cell lines were identified that respond to IL-22 by activation of STATs 1, 3, and 5 PMID:10954742 Recombinant human IL-TIF was found to activate signal transducer and activator of transcription factors-1 and -3 in several hepatoma cell lines. |
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