Existing Annotations Review

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: IL-22 is definitively localized to the extracellular space as a secreted cytokine. The protein contains a signal peptide (aa 1-33) that directs it through the secretory pathway, and mature IL-22 functions in the extracellular environment where it binds to receptors on target cells. The IBA annotation is well-supported by phylogenetic conservation. Reason: IL-22 is a secreted protein that functions in the extracellular space. Multiple structural and functional studies confirm its extracellular localization, including crystal structures of IL-22 bound to its receptor and functional assays showing it acts on cell surface receptors. This is a core aspect of IL-22 biology. Supporting Evidence: file:human/IL22/IL22-uniprot.txt Subcellular location: Secreted. [Signal peptide prediction based on analysis of experimentally verified cleavage sites - PROTEIN SEQUENCE OF 34-48] file:human/IL22/IL22-deep-research.md IL-22 is a secreted protein. It contains an N-terminal signal peptide (amino acids 1–33) 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. 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 IL-22 can also have pro-inflammatory properties – for example, by sustaining chronic inflammation in autoimmune diseases... IL-22 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. While IL-22 does activate signal transduction pathways (JAK-STAT, MAPK, PI3K/AKT) in target cells, this annotation lacks specificity. More precise terms describing IL-22 receptor binding or cytokine-mediated signaling would be more informative. Reason: This overly broad term provides little functional information. IL-22 specifically activates JAK-STAT signaling through its receptor complex. More specific annotations like "cytokine-mediated signaling pathway" (GO:0019221) or "JAK-STAT cascade" (GO:0007259) would be more appropriate. Proposed replacements: cytokine-mediated signaling pathway cell surface receptor signaling pathway via JAK-STAT 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 RecName: Full=Interleukin-22; Short=IL-22; AltName: Full=Cytokine Zcyto18
GO:0005576 extracellular region	IEA GO_REF:0000120	ACCEPT	Summary: Correct localization annotation. IL-22 functions in the extracellular region as a secreted cytokine. This broader term (extracellular region) is appropriate alongside the more specific extracellular space annotation. Reason: IL-22 is correctly annotated to the extracellular region. As a secreted cytokine, it functions outside cells in the extracellular environment. This annotation is consistent with experimental evidence and complements the more specific extracellular space annotation. 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: Duplicate annotation of extracellular space localization via automated methods. While correct, this duplicates the IBA annotation which has stronger phylogenetic support. Reason: Correct annotation supported by multiple lines of evidence. IL-22 is a secreted protein that functions in the extracellular space. Multiple evidence codes for the same correct annotation provide complementary support. Supporting Evidence: file:human/IL22/IL22-uniprot.txt Subcellular location: Secreted.
GO:0005515 protein binding	IPI PMID:12513909 Comparison of interleukin-22 and interleukin-10 soluble rece...	MODIFY	Summary: Generic protein binding annotation that provides minimal functional information. IL-22 specifically binds IL-22R1 and IL-10RB receptors. This should be replaced with the more specific "interleukin-22 receptor binding" term. Reason: While IL-22 does bind proteins (its receptors), the generic "protein binding" term is uninformative. The specific annotation "interleukin-22 receptor binding" (GO:0045518) or "cytokine receptor binding" (GO:0005126) would be more appropriate and informative. Proposed replacements: interleukin-22 receptor binding cytokine receptor binding 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.	MODIFY	Summary: Generic protein binding annotation from structural study of IL-22/IL-22R1 complex. Should be replaced with specific receptor binding annotation. Reason: This paper specifically describes the crystal structure of IL-22 bound to IL-22R1, demonstrating specific receptor binding rather than generic protein binding. The annotation should use "interleukin-22 receptor binding" (GO:0045518). Proposed replacements: interleukin-22 receptor binding 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...	MODIFY	Summary: Another generic protein binding annotation from IL-22/IL-22R1 structural study. Should specify receptor binding. Reason: This paper describes the crystal structure of the IL-22/IL-22R1 complex and signaling mechanism, demonstrating specific receptor binding. Should use "interleukin-22 receptor binding" (GO:0045518) instead of generic protein binding. Proposed replacements: interleukin-22 receptor binding 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...	MODIFY	Summary: Generic protein binding annotation describing IL-10RB interaction. Should specify receptor binding activity. Reason: This paper describes receptor sharing by IL-10R2 (IL-10RB), which is part of the IL-22 receptor complex. The annotation should specify "interleukin-22 receptor binding" or "cytokine receptor binding" rather than generic protein binding. Proposed replacements: interleukin-22 receptor binding cytokine receptor binding 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 anti-inflammatory cytokines like IL-10 or regulatory T cells can suppress IL-22 production [glucocorticoids act similarly as anti-inflammatory agents]
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 IL-22 serves as a key mediator of the innate immune response (GO:0045087) and the inflammatory response (GO:0006954) during infection and injury.
GO:0045518 interleukin-22 receptor binding	NAS PMID:10875937 Interleukin (IL)-22, a novel human cytokine that signals thr...	ACCEPT	Summary: IL-22 specifically binds to the IL-22 receptor complex composed of IL-22R1 (IL-22RA1) and IL-10RB (IL-10R2). This is a core molecular function that has been extensively characterized through structural and biochemical studies. Reason: Interleukin-22 receptor binding is a defining molecular function of IL-22. The protein binds with high affinity to IL-22R1 and forms a signaling complex with IL-10RB. This specific receptor binding activity distinguishes IL-22 from other IL-10 family members and is essential for all IL-22 biological functions. 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 α-chain on epithelial and stromal cells) and the shared IL-10RB (IL-10R2) β-chain.
GO:0050832 defense response to fungus	IC file:human/IL22/IL22-deep-research.md	NEW	Summary: IL-22 mediates defense responses against fungal pathogens at barrier surfaces by inducing antimicrobial peptides. This function is directly stated in the deep research but not currently annotated. Reason: IL-22 plays a documented role in antifungal defense through antimicrobial peptide induction. The deep research explicitly states IL-22 strengthens barriers against both bacteria AND fungi, but only bacterial defense is currently annotated. Supporting Evidence: file:human/IL22/IL22-deep-research.md IL-22 stimulates epithelial cells (in the skin, gut, lung, etc.) to produce antimicrobial peptides (such as β-defensins, S100 proteins, Reg3 lectins in mice) and mucus, thereby strengthening the barrier against pathogenic bacteria and fungi
GO:0010631 epithelial cell migration	IC file:human/IL22/IL22-deep-research.md	NEW	Summary: IL-22 promotes epithelial cell migration and spreading, which is important for wound healing and tissue repair. This is a direct effect of IL-22 signaling. Reason: IL-22 directly promotes epithelial cell migration through its signaling pathways. This is distinct from proliferation and is an important component of wound healing. Supporting Evidence: file:human/IL22/IL22-deep-research.md epithelial cell migration (IL-22 was shown to promote epithelial cell spreading and mobility)
GO:0043066 negative regulation of apoptotic process	IC file:human/IL22/IL22-deep-research.md	NEW	Summary: IL-22 promotes cell survival and protects cells from apoptosis, particularly in hepatocytes and epithelial cells. This anti-apoptotic effect is mediated through STAT3 activation and upregulation of survival proteins. Reason: Cell survival/anti-apoptosis is a core function of IL-22, particularly important for its tissue-protective effects. Multiple studies demonstrate IL-22 prevents apoptosis in target cells. Supporting Evidence: file:human/IL22/IL22-deep-research.md These signaling cascades promote target cell survival, proliferation, and repair, enabling tissues to withstand and recover from inflammatory damage file:human/IL22/IL22-deep-research.md IL-22 acts as a survival factor for hepatocytes via STAT3 activation, reducing liver damage... In vitro, IL-22 could prevent hepatocyte apoptosis file:human/IL22/IL22-deep-research.md linking this cytokine to numerous gene expression programs involved in inflammation, cell survival (e.g. upregulating Bcl-2/Bcl-x_L)
GO:0070257 positive regulation of mucus secretion	IC file:human/IL22/IL22-deep-research.md	NEW	Summary: IL-22 stimulates mucus production by epithelial cells at barrier surfaces, which is an important component of antimicrobial defense and barrier function. Reason: Mucus production is specifically mentioned as an IL-22-induced protective mechanism at mucosal barriers. This is distinct from antimicrobial peptide production and represents an important barrier defense function. Supporting Evidence: file:human/IL22/IL22-deep-research.md IL-22 stimulates epithelial cells (in the skin, gut, lung, etc.) to produce antimicrobial peptides (such as β-defensins, S100 proteins, Reg3 lectins in mice) and mucus, thereby strengthening the barrier against pathogenic bacteria and fungi file:human/IL22/IL22-deep-research.md IL-22 plays a paradoxical role: it is generally protective for the intestinal mucosa (promoting wound healing and mucus production)
GO:0072089 stem cell proliferation	IC file:human/IL22/IL22-deep-research.md	NEW	Summary: IL-22 promotes intestinal stem cell proliferation, which is crucial for epithelial regeneration after injury. This is a specific and important function distinct from general epithelial proliferation. Reason: IL-22 specifically drives stem cell proliferation in the intestine, which is mechanistically distinct from differentiated epithelial cell proliferation. This function is key to IL-22s regenerative capacity. Supporting Evidence: file:human/IL22/IL22-deep-research.md IL-22 has been shown to drive intestinal stem cell proliferation and epithelial regeneration after acute injury in the gut, largely via STAT3 activation in those cells
GO:0002225 positive regulation of antimicrobial peptide production	IEA	NEW	Summary: IL-22 stimulates epithelial cells to produce antimicrobial peptides such as β-defensins, S100 proteins, and Reg3 lectins at mucosal surfaces as part of barrier defense Reason: This is a hallmark function of IL-22 at mucosal surfaces, where it strengthens epithelial barriers by inducing antimicrobial peptide production in skin, gut, and lung epithelial cells Supporting Evidence: file:human/IL22/IL22-deep-research.md IL-22 stimulates epithelial cells (in the skin, gut, lung, etc.) to produce antimicrobial peptides (such as β-defensins, S100 proteins, Reg3 lectins in mice) and mucus, thereby strengthening the barrier against pathogenic bacteria and fungi
GO:0042060 wound healing	IEA	NEW	Summary: IL-22 promotes epithelial regeneration for wound healing Reason: IL-22 plays an essential role in regenerating epithelial cells after injury to maintain barrier function and prevent further tissue damage. It induces proliferation and antimicrobial peptide production in keratinocytes and intestinal epithelial cells. Supporting Evidence: PMID:17204547 IL-22-mediated liver cell regeneration
GO:0042742 defense response to bacterium	IEA	NEW	Summary: IL-22 induces antimicrobial peptides for bacterial defense Reason: IL-22 induces production of antimicrobial peptides (β-defensins, S100 proteins, RegIIIγ) in epithelial cells at mucosal surfaces. This provides critical defense against bacterial pathogens at barrier sites like intestine and lung. Supporting Evidence: file:human/IL22/IL22-deep-research.md IL-22 induces antimicrobial peptide production
GO:0045087 innate immune response	IEA	NEW	Summary: IL-22 mediates innate immunity at epithelial barriers Reason: IL-22 is a key mediator of innate immunity at epithelial surfaces, inducing antimicrobial peptide production and maintaining barrier integrity. Unlike other cytokines, IL-22 acts on tissue cells rather than immune cells to coordinate innate defense. Supporting Evidence: file:human/IL22/IL22-deep-research.md IL-22 targets epithelial cells rather than immune cells
GO:0050673 epithelial cell proliferation	IEA	NEW	Summary: IL-22 induces epithelial cell proliferation for tissue repair Reason: IL-22 directly stimulates proliferation of epithelial cells including keratinocytes, intestinal epithelial cells, and hepatocytes. This proliferative response is essential for tissue regeneration and barrier restoration after injury. Supporting Evidence: PMID:17204547 IL-22-mediated liver cell regeneration
GO:0007259 cell surface receptor signaling pathway via JAK-STAT	IEA	NEW	Summary: IL-22 binding to its heterodimeric receptor (IL-22RA1/IL-10RB) activates JAK1 and TYK2 tyrosine kinases, leading to STAT3 phosphorylation and downstream signaling Reason: The JAK-STAT pathway (particularly STAT3) is the central and primary signaling mechanism triggered by IL-22 upon receptor binding, essential for all IL-22 functions Supporting Evidence: file:human/IL22/IL22-deep-research.md Upon ligand binding, this receptor activates the JAK1 and TYK2 tyrosine kinases, leading to phosphorylation of STAT3 and downstream signaling via the ERK, PI3K/AKT, and STAT3 pathways. The JAK-STAT pathway (particularly STAT3) is the central pathway triggered by IL-22

Core Functions

Interleukin-22 receptor binding activates JAK-STAT signaling in epithelial cells to induce antimicrobial peptide production

Molecular Function:

interleukin-22 receptor binding

Directly Involved In:

positive regulation of antimicrobial peptide production defense response to bacterium cell surface receptor signaling pathway via JAK-STAT

Cellular Locations:

extracellular region

Supporting Evidence:

file:human/IL22/IL22-deep-research.md
IL-22 stimulates epithelial cells (in the skin, gut, lung, etc.) to produce antimicrobial peptides (such as β-defensins, S100 proteins, Reg3 lectins in mice) and mucus, thereby strengthening the barrier against pathogenic bacteria and fungi
PMID:10875937
Cell lines were identified that respond to IL-22 by activation of STATs 1, 3, and 5

Cytokine activity stimulates hepatocyte acute phase protein synthesis through STAT3 activation

Molecular Function:

cytokine activity

Directly Involved In:

acute-phase response inflammatory response

Cellular Locations:

extracellular region

Interleukin-22 receptor binding promotes epithelial cell proliferation and tissue repair at barrier surfaces

Molecular Function:

interleukin-22 receptor binding

Directly Involved In:

epithelial cell proliferation wound healing innate immune response

Cellular Locations:

extracellular region

Supporting Evidence:

file:human/IL22/IL22-deep-research.md
IL-22 promotes proliferation and survival of epithelial cells, aiding in wound healing of damaged tissues... IL-22 has been shown to drive intestinal stem cell proliferation and epithelial regeneration after acute injury in the gut, largely via STAT3 activation

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links.

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods.

PMID:10875937

Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R.

PMID:10954742

Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor.

PMID:11481447

A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist.

PMID:12513909

Comparison of interleukin-22 and interleukin-10 soluble receptor complexes.

PMID:18599299

Structure of IL-22 bound to its high-affinity IL-22R1 chain.

PMID:18675809

Crystal structure of the IL-22/IL-22R1 complex and its implications for the IL-22 signaling mechanism.

PMID:20462497

Structure and mechanism of receptor sharing by the IL-10R2 common chain.

Reactome:R-HSA-448480

IL22 binds IL22RA1:JAK1 receptor complex

Reactome:R-HSA-448741

IL22RA2 binds IL22

Reactome:R-HSA-8854645

IL22:IL22RA1:JAK1 binds IL10RB:TYK2

Reactome:R-HSA-8986995

IL22:IL22RA1:p-JAK1:IL10RB:p-TYK2 phosphorylates IL22RA

Reactome:R-HSA-8987014

IL22:p-Y251,p-Y301-IL22RA1:p-JAK1:PTPN11:IL10RB:p-TYK2 binds STAT3

Reactome:R-HSA-8987042

IL22:IL22RA1:JAK1:IL10RB:TYK2 phosphorylates JAK1,TYK2

Reactome:R-HSA-8987070

IL22:p-Y251,p-Y301-IL22RA1:p-JAK1:IL10RB:p-TYK2:STAT3 phosphorylates STAT3

Reactome:R-HSA-8987132

IL22:p‑Y251,p‑Y301‑IL22RA1:p‑JAK1:PTPN11:IL10RB:p‑TYK2 binds PTPN11

Reactome:R-HSA-8987236

p-Y705-STAT3 dissociates from IL22:p-Y251,p-Y301-IL22RA1:p-JAK1:IL10RB:p-TYK2:p-Y705-STAT3

file:human/IL22/IL22-deep-research.md

IL22 Deep Research Report (AI-generated synthesis)

Deep Research

Falcon

(IL22-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 26 citations 2026-02-08T20:32:49.050816

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

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

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

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

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

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

Comprehensive research report: Human IL-22 (IL22; UniProt Q9GZX6)

Identity verification and scope
- Gene/protein check: The request targets human IL-22 (IL22; UniProt Q9GZX6), a secreted IL-10 family cytokine with a four-helix bundle fold. Literature consistently identifies IL-22 as an IL-10 family cytokine acting primarily on non-hematopoietic epithelial and parenchymal cells, matching the UniProt family/domain context and organism (Homo sapiens) provided. Foundational reviews and disease-focused summaries align on receptor usage, signaling, and epithelial tropism (publication URLs and dates below) (zenewicz2011recentadvancesin pages 3-3, zenewicz2011recentadvancesin pages 1-1, mizoguchi2012healingofintestinal pages 2-4, aebisher2024keyinterleukinsin pages 7-9, aebisher2024keyinterleukinsin pages 9-11).

Key concepts and definitions (current understanding)
- Cytokine family and structure: IL-22 is a member of the IL-10 cytokine family; it is an α-helical, secreted cytokine that targets epithelial barriers (International Immunology, Mar 2011; https://doi.org/10.1093/intimm/dxr001) (zenewicz2011recentadvancesin pages 3-3, zenewicz2011recentadvancesin pages 1-1).
- Receptor composition and target-cell restriction: IL-22 signals via a class II cytokine receptor heterodimer composed of IL-22R1 and IL-10R2 (IL-10Rβ). IL-22R1 expression is largely restricted to non-hematopoietic cells (e.g., intestinal epithelium, keratinocytes, hepatocytes), explaining tissue-targeted effects (Inflammatory Bowel Diseases, Sep 2012; https://doi.org/10.1002/ibd.22929) (mizoguchi2012healingofintestinal pages 2-4, mizoguchi2012healingofintestinal pages 7-9).
- Signaling: Engagement of IL-22R1/IL-10R2 activates JAK1 and TYK2, dominantly signaling through STAT3, with context-dependent activation of STAT1/STAT5. STAT3 drives epithelial survival, proliferation, and repair programs (IJMS, Dec 2024; https://doi.org/10.3390/ijms26010121) (aebisher2024keyinterleukinsin pages 7-9, aebisher2024keyinterleukinsin pages 9-11).
- Cellular sources: Principal producers include adaptive Th22 and Th17 CD4+ T cells, and innate lymphoid cells (ILC3/LTi-like), with contributions from γδ T cells and NK/NKT cells; AHR and IL-23–related circuits regulate production depending on tissue and inflammation (Mar 2011; https://doi.org/10.1093/intimm/dxr001; Sep 2012; https://doi.org/10.1002/ibd.22929) (zenewicz2011recentadvancesin pages 1-1, mizoguchi2012healingofintestinal pages 2-4).
- Localization and regulation: IL-22 is secreted and acts on nearby epithelial/parenchymal targets. Activity is buffered by a high-affinity soluble decoy receptor, IL-22 binding protein (IL-22BP/IL22RA2), which neutralizes IL-22 and is dynamically regulated in gut inflammation (Sep 2012; https://doi.org/10.1002/ibd.22929; IJMS, Dec 2024; https://doi.org/10.3390/ijms26010121) (mizoguchi2012healingofintestinal pages 7-9, aebisher2024keyinterleukinsin pages 9-11).
- Core epithelial/repair functions: IL-22 induces antimicrobial peptides (e.g., Reg, β-defensins), mucins, and tight-junction/barrier programs; it stimulates epithelial proliferation and wound healing in gut and skin and promotes hepatocyte survival via STAT3 (Mar 2011; https://doi.org/10.1093/intimm/dxr001; Sep 2012; https://doi.org/10.1002/ibd.22929) (zenewicz2011recentadvancesin pages 3-3, zenewicz2011recentadvancesin pages 3-4).

Feature	Key facts	Main source(s)
Identity & family	Member of the IL-10 cytokine family; alpha-helical, secreted cytokine.	Zenewicz 2011 (zenewicz2011recentadvancesin pages 3-3)
Cellular sources	Produced by Th22/Th17 CD4+ T cells, ILC3, γδ T cells, NK/NKT and some neutrophils.	Zenewicz 2011 (zenewicz2011recentadvancesin pages 3-3), Mizoguchi 2012 (mizoguchi2012healingofintestinal pages 2-4)
Receptor	Signals via a heterodimeric receptor: IL-22R1 + IL-10R2 (IL-10Rβ), receptor largely on non-hematopoietic cells.	Mizoguchi 2012 (mizoguchi2012healingofintestinal pages 2-4)
Signaling	Activates JAK1/TYK2 → STATs (primarily STAT3; can engage STAT1/5), driving proliferation and survival programs.	Aebisher 2024 (aebisher2024keyinterleukinsin pages 9-11), Zenewicz 2011 (zenewicz2011recentadvancesin pages 3-3)
Target cells/tissues	Acts on epithelial and stromal (non-hematopoietic) cells in gut, skin, lung, liver, pancreas and other barrier tissues.	Zenewicz 2011 (zenewicz2011recentadvancesin pages 3-3), Mizoguchi 2012 (mizoguchi2012healingofintestinal pages 2-4)
Localization	Secreted cytokine that acts extracellularly on nearby epithelial/parenchymal cells.	Zenewicz 2011 (zenewicz2011recentadvancesin pages 1-1)
Regulation by IL-22BP	Neutralized by a high-affinity soluble decoy IL-22 binding protein (IL22RA2/IL-22BP) that limits IL-22 activity in tissues.	Mizoguchi 2012 (mizoguchi2012healingofintestinal pages 7-9), Aebisher 2024 (aebisher2024keyinterleukinsin pages 9-11)
Core functions	Promotes barrier integrity: antimicrobial peptide and mucin induction, epithelial proliferation, wound healing and tissue repair.	Zenewicz 2011 (zenewicz2011recentadvancesin pages 3-3), Mizoguchi 2012 (mizoguchi2012healingofintestinal pages 2-4)
Pathogenic roles	Chronic or excessive IL-22 can drive epithelial hyperplasia, contribute to psoriasis/AD-like pathology, and context-dependent inflammation.	Zenewicz 2011 (zenewicz2011recentadvancesin pages 3-3), Aebisher 2024 (aebisher2024keyinterleukinsin pages 9-11)
Disease areas	Implicated in IBD (UC/CD), atopic dermatitis, psoriasis, alcoholic hepatitis/MASH/MASLD, aGVHD and epithelial cancers (context-dependent).	Aebisher 2024 (aebisher2024keyinterleukinsin pages 7-9, aebisher2024keyinterleukinsin pages 9-11), Mizoguchi 2012 (mizoguchi2012healingofintestinal pages 2-4)
Therapeutic strategies	Both agonists (long-acting IL-22Fc/IL-22 fusion proteins) and antagonists (anti-IL-22 mAbs) are in translational/clinical investigation.	Aebisher 2024 (aebisher2024keyinterleukinsin pages 9-11), Mizoguchi 2012 (mizoguchi2012healingofintestinal pages 2-4)

Table: A concise reference table summarizing IL-22 identity, sources, signaling, functions, pathological roles, disease relevance, and therapeutic approaches with primary citations for quick consultation.

Recent developments and latest research (2023–2024 emphasis)
- IBD and mucosal immunity: A 2024 review synthesizes 2022–2024 studies, reaffirming IL-22’s epithelial-repair actions via JAK1/TYK2→STAT3 and detailing IL-22BP as a physiological antagonist that can blunt IL-22-driven mucosal healing. It highlights context-dependent outcomes (protective in acute injury; potential inflammation/proliferation if dysregulated) and emerging mechanistic insights (Paneth cell support; impacts on epithelial differentiation and mucin biology) (IJMS, Dec 2024; https://doi.org/10.3390/ijms26010121) (aebisher2024keyinterleukinsin pages 7-9, aebisher2024keyinterleukinsin pages 9-11).
- Liver disease and biomarkers: Reviews in 2024 discuss IL-22 as part of biomarker panels and as a therapeutic pathway in liver failure and alcoholic hepatitis, reflecting its hepatocyte-protective, anti-apoptotic STAT3 programs; they note evaluation of IL-22–based interventions and prognostic value of interleukins including IL-22 (World Journal of Clinical Cases, Sep 2024; https://doi.org/10.12998/wjcc.v12.i27.6045) ().
- MASLD/MASH: A 2024 review underscores a largely protective signature for IL-22 in metabolic liver disease models and discusses translational testing of IL-22 as a therapeutic strategy in MASLD, contrasting it with pro-fibrogenic IL-17 effects (Frontiers in Immunology, Aug 2024; https://doi.org/10.3389/fimmu.2024.1437046) (zenewicz2011recentadvancesin pages 1-1).
- Extraintestinal/oncology context: 2024 analyses explore IL-22 in tumor microenvironments (e.g., lung cancer), consolidating receptor biology and potential biomarker/therapeutic targeting roles, though clinical utility remains investigational (Heliyon, Sep 2024; https://doi.org/10.1016/j.heliyon.2024.e35901) (zenewicz2011recentadvancesin pages 3-3).

Current applications and real-world/translational implementations
- Antagonism in atopic dermatitis (AD): Phase 2 data (NCT01941537) for the anti–IL-22 monoclonal antibody fezakinumab (ILV-094) in adults with moderate-to-severe AD reported differential outcomes over time. Mean SCORAD change at Week 12: −13.8 with fezakinumab vs −8.0 with placebo (p=0.134); at Week 20: −18.8 vs −11.7 (p=0.049), indicating a later emerging separation. This trial enrolled 60 adults (Biomolecules, Jun 2025; https://doi.org/10.3390/biom15060838). While published in 2025, it synthesizes earlier trial results and translational analyses that inform 2023–2024 clinical thinking. Safety details were not provided in the excerpt; biomarker-responder signatures (e.g., “fezakinumab response” subsets) have been discussed in the AD translational literature and reviews (lo2025advancingtherapeuticstrategies pages 8-10).
- Agonism in GI and liver indications: Contemporary reviews (2024) describe the rationale and ongoing clinical exploration of long-acting IL-22 fusion proteins (e.g., IL-22–Fc formats) to enhance epithelial repair in ulcerative colitis and to protect hepatocytes in alcoholic hepatitis/acute-on-chronic liver contexts; they emphasize STAT3-mediated cytoprotective programs and the need to mitigate epithelial hyperproliferation risks by dose/regional targeting (IJMS, Dec 2024; https://doi.org/10.3390/ijms26010121; World Journal of Clinical Cases, Sep 2024; https://doi.org/10.12998/wjcc.v12.i27.6045; Frontiers in Immunology, Aug 2024; https://doi.org/10.3389/fimmu.2024.1437046) (aebisher2024keyinterleukinsin pages 9-11, zenewicz2011recentadvancesin pages 1-1).

Expert opinions and analysis (authoritative sources)
- Consensus on epithelial tropism and duality: Authoritative reviews emphasize IL-22’s dual nature—protective in acute epithelial injury through antimicrobial induction and proliferation, yet potentially pathogenic with chronic overexpression (psoriasiform changes, context-dependent inflammation). This duality supports a precision approach: antagonize in diseases of epithelial hyperproliferation (e.g., subsets of AD/psoriasis), and agonize in barrier failure and hepatocellular injury (Mar 2011; https://doi.org/10.1093/intimm/dxr001; Sep 2012; https://doi.org/10.1002/ibd.22929; IJMS, Dec 2024; https://doi.org/10.3390/ijms26010121) (zenewicz2011recentadvancesin pages 3-3, zenewicz2011recentadvancesin pages 3-4, aebisher2024keyinterleukinsin pages 7-9, aebisher2024keyinterleukinsin pages 9-11).
- Regulatory buffering by IL-22BP: Experts highlight IL-22BP as a critical tissue checkpoint that can be induced during inflammation (e.g., by TNF) to limit IL-22’s reparative STAT3 signaling; therapeutic strategies must consider IL-22BP dynamics to avoid blunting desired repair or, conversely, to restrain excessive proliferation (Sep 2012; https://doi.org/10.1002/ibd.22929; IJMS, Dec 2024; https://doi.org/10.3390/ijms26010121) (mizoguchi2012healingofintestinal pages 7-9, aebisher2024keyinterleukinsin pages 9-11).
- Tissue-selective targeting and safety: Recent analyses argue for cell- or organ-targeted IL-22 agonists and careful patient selection for antagonists (e.g., AD endotypes), acknowledging risks of epithelial hyperplasia and theoretical neoplasia with prolonged STAT3 activation. This is consistent with historic transgenic and mechanistic data (Mar 2011; https://doi.org/10.1093/intimm/dxr001; Dec 2024; https://doi.org/10.3390/ijms26010121) (zenewicz2011recentadvancesin pages 3-3, aebisher2024keyinterleukinsin pages 9-11).

Relevant statistics and data from recent studies
- AD antagonism (fezakinumab/ILV-094): Phase 2 randomized trial (adults, n=60). SCORAD change: Week 12 −13.8 vs −8.0 (p=0.134); Week 20 −18.8 vs −11.7 (p=0.049). Interpretation: modest, delayed clinical separation; responder stratification remains an active area for biomarker-led selection (Biomolecules, Jun 2025; https://doi.org/10.3390/biom15060838) (lo2025advancingtherapeuticstrategies pages 8-10).
- IBD and barrier metrics: 2024 synthesis reiterates STAT3-centric epithelial responses (tight junction reinforcement, antimicrobial peptides, mucins) as measurable pharmacodynamic endpoints for IL-22 agonism, with IL-22BP levels and epithelial program readouts as translational biomarkers (IJMS, Dec 2024; https://doi.org/10.3390/ijms26010121) (aebisher2024keyinterleukinsin pages 7-9, aebisher2024keyinterleukinsin pages 9-11).
- Liver disease: 2024 liver-focused reviews note exploration of IL-22 in prognostic biomarker panels for liver failure and emphasize evaluation of IL-22–based interventions in alcoholic hepatitis/related conditions; clinical endpoints typically include MELD/Lille scores and short-term mortality/organ function in these indications (World Journal of Clinical Cases, Sep 2024; https://doi.org/10.12998/wjcc.v12.i27.6045) ().

Functional annotation summary (mechanisms, processes, localization)
- Primary function: IL-22 is a secreted cytokine messenger from Th22/Th17/ILC3 and related lymphocytes that signals via IL-22R1/IL-10R2 on non-hematopoietic epithelial/parenchymal cells to activate JAK1/TYK2→STAT3 and related pathways. This induces antimicrobial, mucus, tight-junction, and proliferative/repair programs that restore barrier integrity and support tissue survival, particularly in gut, skin, lung, and liver (2011–2012 mechanistic foundation; 2024 updates) (zenewicz2011recentadvancesin pages 3-3, zenewicz2011recentadvancesin pages 1-1, mizoguchi2012healingofintestinal pages 2-4, aebisher2024keyinterleukinsin pages 7-9, aebisher2024keyinterleukinsin pages 9-11).
- Cellular/cellular-compartment localization: Secreted; acts on epithelial targets (keratinocytes, intestinal epithelial cells, airway epithelium) and parenchymal cells such as hepatocytes. Notably, hematopoietic cells generally lack IL-22R1, conferring tissue selectivity (Sep 2012; https://doi.org/10.1002/ibd.22929) (mizoguchi2012healingofintestinal pages 2-4, mizoguchi2012healingofintestinal pages 7-9).
- Pathway role: A type-3 immunity effector that complements IL-17 biology; IL-22’s dominant output is epithelial protection/repair, counterbalanced by IL-22BP and context-specific cytokine milieus (e.g., IL-17A/IFN-γ can modulate outcomes) (Sep 2012; https://doi.org/10.1002/ibd.22929; Aug 2024; https://doi.org/10.3389/fimmu.2024.1437046) (mizoguchi2012healingofintestinal pages 7-9, zenewicz2011recentadvancesin pages 1-1).

Major disease areas (representative evidence)
- IBD (UC/CD): Elevated IL-22 in active disease; protective epithelial repair vs potential chronic proinflammatory effects are context-dependent; IL-22BP induction can hinder mucosal healing, suggesting therapeutic windows for agonism or IL-22BP modulation (IJMS, Dec 2024; https://doi.org/10.3390/ijms26010121) (aebisher2024keyinterleukinsin pages 7-9, aebisher2024keyinterleukinsin pages 9-11).
- Atopic dermatitis/psoriasis: IL-22 drives keratinocyte hyperplasia and barrier dysfunction in subsets; anti–IL-22 therapy shows signals in severe AD populations with late divergence, motivating biomarker-led patient selection (Int Immunol, Mar 2011; https://doi.org/10.1093/intimm/dxr001; Biomolecules, Jun 2025; https://doi.org/10.3390/biom15060838) (zenewicz2011recentadvancesin pages 3-3, lo2025advancingtherapeuticstrategies pages 8-10).
- Alcoholic hepatitis/acute liver failure spectrum and MASLD/MASH: Preclinical and translational analyses position IL-22 as hepatoprotective via STAT3; 2024 reviews document ongoing evaluation and biomarker roles (World Journal of Clinical Cases, Sep 2024; https://doi.org/10.12998/wjcc.v12.i27.6045; Frontiers in Immunology, Aug 2024; https://doi.org/10.3389/fimmu.2024.1437046) (zenewicz2011recentadvancesin pages 1-1).
- Neuro/oncology exploratory contexts: Associations with glial activation and tumor microenvironments are reported but remain investigational for clinical translation (Frontiers in Pharmacology, Sep 2022; https://doi.org/10.3389/fphar.2022.958022; Heliyon, Sep 2024; https://doi.org/10.1016/j.heliyon.2024.e35901) (chen2022interleukin22and pages 1-2, zenewicz2011recentadvancesin pages 3-3).

Notes on limitations and data gaps
- While 2023–2024 reviews and analyses provide strong mechanistic and translational grounding, head-to-head and large late-phase clinical data in IL-22 agonism (e.g., epithelial indications) remain limited in the excerpts retrieved here. Reported AD antagonism results (fezakinumab) suggest modest but potentially endotype-specific efficacy, underscoring the importance of biomarker-led trial designs and endpoint timing (lo2025advancingtherapeuticstrategies pages 8-10). Future targeted-delivery approaches and careful attention to IL-22BP and STAT3-driven proliferation risks are recurrent expert themes (aebisher2024keyinterleukinsin pages 9-11, zenewicz2011recentadvancesin pages 3-3).

References with URLs and dates
- Zenewicz LA, Flavell R. Recent advances in IL-22 biology. International Immunology. Mar 2011. URL: https://doi.org/10.1093/intimm/dxr001 (zenewicz2011recentadvancesin pages 3-3, zenewicz2011recentadvancesin pages 1-1).
- Mizoguchi A. Healing of intestinal inflammation by IL‑22. Inflammatory Bowel Diseases. Sep 2012. URL: https://doi.org/10.1002/ibd.22929 (mizoguchi2012healingofintestinal pages 2-4, mizoguchi2012healingofintestinal pages 7-9, zenewicz2011recentadvancesin pages 3-4).
- Aebisher D et al. Key interleukins in inflammatory bowel disease—a review of recent studies. International Journal of Molecular Sciences. Dec 2024. URL: https://doi.org/10.3390/ijms26010121 (aebisher2024keyinterleukinsin pages 7-9, aebisher2024keyinterleukinsin pages 9-11).
- Lin Y et al. Review of the potential value of serum interleukin levels as prognostic biomarkers of liver failure. World Journal of Clinical Cases. Sep 2024. URL: https://doi.org/10.12998/wjcc.v12.i27.6045 ().
- Abdelnabi MN et al. Role of the type 3 cytokines IL‑17 and IL‑22 in modulating MASLD. Frontiers in Immunology. Aug 2024. URL: https://doi.org/10.3389/fimmu.2024.1437046 (zenewicz2011recentadvancesin pages 1-1).
- Xu L et al. IL‑22: biomarker and potential therapeutic target for lung cancer. Heliyon. Sep 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e35901 (zenewicz2011recentadvancesin pages 3-3).
- Chen W et al. Interleukin‑22 and neurodegenerative disease activity. Frontiers in Pharmacology. Sep 2022. URL: https://doi.org/10.3389/fphar.2022.958022 (chen2022interleukin22and pages 1-2).
- Lo Y et al. Advancing therapeutic strategies in atopic dermatitis: emerging targets and personalized approaches. Biomolecules. Jun 2025. URL: https://doi.org/10.3390/biom15060838 (phase 2 fezakinumab data summarized) (lo2025advancingtherapeuticstrategies pages 8-10).

References

(zenewicz2011recentadvancesin pages 3-3): Lauren A. Zenewicz and R. Flavell. Recent advances in il-22 biology. International immunology, 23 3:159-63, Mar 2011. URL: https://doi.org/10.1093/intimm/dxr001, doi:10.1093/intimm/dxr001. This article has 464 citations and is from a peer-reviewed journal.
(zenewicz2011recentadvancesin pages 1-1): Lauren A. Zenewicz and R. Flavell. Recent advances in il-22 biology. International immunology, 23 3:159-63, Mar 2011. URL: https://doi.org/10.1093/intimm/dxr001, doi:10.1093/intimm/dxr001. This article has 464 citations and is from a peer-reviewed journal.
(mizoguchi2012healingofintestinal pages 2-4): Atsushi Mizoguchi. Healing of intestinal inflammation by il‐22. Inflammatory Bowel Diseases, 18:1777–1784, Sep 2012. URL: https://doi.org/10.1002/ibd.22929, doi:10.1002/ibd.22929. This article has 173 citations and is from a domain leading peer-reviewed journal.
(aebisher2024keyinterleukinsin pages 7-9): David Aebisher, Dorota Bartusik-Aebisher, Agnieszka Przygórzewska, Piotr Oleś, Paweł Woźnicki, and Aleksandra Kawczyk-Krupka. Key interleukins in inflammatory bowel disease—a review of recent studies. International Journal of Molecular Sciences, 26:121, Dec 2024. URL: https://doi.org/10.3390/ijms26010121, doi:10.3390/ijms26010121. This article has 29 citations and is from a poor quality or predatory journal.
(aebisher2024keyinterleukinsin pages 9-11): David Aebisher, Dorota Bartusik-Aebisher, Agnieszka Przygórzewska, Piotr Oleś, Paweł Woźnicki, and Aleksandra Kawczyk-Krupka. Key interleukins in inflammatory bowel disease—a review of recent studies. International Journal of Molecular Sciences, 26:121, Dec 2024. URL: https://doi.org/10.3390/ijms26010121, doi:10.3390/ijms26010121. This article has 29 citations and is from a poor quality or predatory journal.
(mizoguchi2012healingofintestinal pages 7-9): Atsushi Mizoguchi. Healing of intestinal inflammation by il‐22. Inflammatory Bowel Diseases, 18:1777–1784, Sep 2012. URL: https://doi.org/10.1002/ibd.22929, doi:10.1002/ibd.22929. This article has 173 citations and is from a domain leading peer-reviewed journal.
(zenewicz2011recentadvancesin pages 3-4): Lauren A. Zenewicz and R. Flavell. Recent advances in il-22 biology. International immunology, 23 3:159-63, Mar 2011. URL: https://doi.org/10.1093/intimm/dxr001, doi:10.1093/intimm/dxr001. This article has 464 citations and is from a peer-reviewed journal.
(lo2025advancingtherapeuticstrategies pages 8-10): Yang Lo, Ting-Ting Cheng, Chi-Jung Huang, Yu-Che Cheng, and I-Tsu Chyuan. Advancing therapeutic strategies in atopic dermatitis: emerging targets and personalized approaches. Biomolecules, 15:838, Jun 2025. URL: https://doi.org/10.3390/biom15060838, doi:10.3390/biom15060838. This article has 5 citations and is from a poor quality or predatory journal.
(chen2022interleukin22and pages 1-2): Wenjian Chen, Jianpeng Wang, Huaizhi Yang, Yuankai Sun, Bangjie Chen, Yuchen Liu, Yanxun Han, Ming Shan, and Junfeng Zhan. Interleukin 22 and its association with neurodegenerative disease activity. Frontiers in Pharmacology, Sep 2022. URL: https://doi.org/10.3389/fphar.2022.958022, doi:10.3389/fphar.2022.958022. This article has 20 citations and is from a poor quality or predatory journal.

Citations

zenewicz2011recentadvancesin pages 3-3
mizoguchi2012healingofintestinal pages 2-4
aebisher2024keyinterleukinsin pages 9-11
zenewicz2011recentadvancesin pages 1-1
mizoguchi2012healingofintestinal pages 7-9
lo2025advancingtherapeuticstrategies pages 8-10
aebisher2024keyinterleukinsin pages 7-9
zenewicz2011recentadvancesin pages 3-4
https://doi.org/10.1093/intimm/dxr001
https://doi.org/10.1002/ibd.22929
https://doi.org/10.3390/ijms26010121
https://doi.org/10.1093/intimm/dxr001;
https://doi.org/10.1002/ibd.22929;
https://doi.org/10.12998/wjcc.v12.i27.6045
https://doi.org/10.3389/fimmu.2024.1437046
https://doi.org/10.1016/j.heliyon.2024.e35901
https://doi.org/10.3390/biom15060838
https://doi.org/10.3390/ijms26010121;
https://doi.org/10.12998/wjcc.v12.i27.6045;
https://doi.org/10.3389/fphar.2022.958022;
https://doi.org/10.3389/fphar.2022.958022
https://doi.org/10.1093/intimm/dxr001,
https://doi.org/10.1002/ibd.22929,
https://doi.org/10.3390/ijms26010121,
https://doi.org/10.3390/biom15060838,
https://doi.org/10.3389/fphar.2022.958022,

Deep Research Report: IL22 (human)

(IL22-deep-research.md)

Deep Research Report: IL22 (human)

Generated using OpenAI Deep Research API

IL22 (Human Interleukin-22) – Comprehensive Gene Report

Gene Function and Molecular Mechanisms

Interleukin-22 (IL-22) is a secreted cytokine in the IL-10 family that plays a pivotal role in modulating immune responses at barrier surfaces (www.ncbi.nlm.nih.gov) (www.genecards.org). Unlike many cytokines, IL-22 primarily acts on non-immune cells (e.g. epithelial cells and hepatocytes) to induce protective and regenerative programs, rather than directly on immune cells (www.genecards.org). IL-22 binds to a heterodimeric receptor complex composed of IL-22RA1 (a cell-type specific α-chain on epithelial and stromal cells) and the shared IL-10RB (IL-10R2) β-chain (www.genecards.org). Upon ligand binding, this receptor activates the JAK1 and TYK2 tyrosine kinases, leading to phosphorylation of STAT3 and downstream signaling via the ERK, PI3K/AKT, and STAT3 pathways (www.genome.jp) (www.genecards.org). These signaling cascades promote target cell survival, proliferation, and repair, enabling tissues to withstand and recover from inflammatory damage (www.genome.jp) (www.genecards.org). IL-22’s mechanism is distinctive in that it has no direct effect on hematopoietic cells, focusing its action on tissue cells at sites of inflammation (www.genecards.org). A unique regulatory aspect of IL-22 biology is the presence of a soluble IL-22 binding protein (IL-22BP, encoded by IL22RA2) that acts as a decoy receptor – IL-22BP can sequester IL-22 and prevent it from signaling, thus buffering IL-22 activity in tissues (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). This IL-22/IL-22BP system allows tight control of IL-22-driven pathways, balancing host defense and tissue damage during immune responses.

Cellular Localization and Structure

Subcellular localization: IL-22 is a secreted protein. It contains an N-terminal signal peptide (amino acids 1–33) that directs it into the endoplasmic reticulum/Golgi secretory pathway, after which the mature cytokine is released into the extracellular space (www.genome.jp) (www.genome.jp). Consequently, the functional location of IL-22 is the extracellular region, where it diffuses to interact with receptors on target cell surfaces. IL-22 is typically found in the extracellular milieu (outside the cell) and is not associated with intracellular organelles or the plasma membrane (except during the secretion process) (www.proteinatlas.org) (www.genome.jp). Consistent with this, Reactome and other pathway databases localize IL-22 to the extracellular region in human pathways (reactome.org). Its receptor subunits IL-22RA1 and IL-10RB are membrane-bound on responsive cells, allowing IL-22 to exert effects in a paracrine manner.

Protein structural features: The IL-22 protein is 179 amino acids in length (precursor form), with the first 33 residues constituting a signal peptide and residues 34–179 comprising the mature cytokine chain (www.genome.jp). It belongs to the class II α-helical cytokine family (the IL-10 family) which share a characteristic four-helix bundle fold (pmc.ncbi.nlm.nih.gov) (www.genome.jp). Indeed, IL-22 is structured as a compact bundle of six α-helices (A–F), of which four (A, C, D, F) form the canonical helical bundle common to IL-10-related cytokines (pmc.ncbi.nlm.nih.gov). Unlike IL-10 (which forms a homodimer), IL-22 functions as a monomeric cytokine, consistent with crystal structures of IL-22 that show it does not form intertwined dimers (pmc.ncbi.nlm.nih.gov). The IL22 protein domain (Pfam: IL22, residues ~40–179) is also known as IL-TIF domain, reflecting its original name “IL-10-related T-cell inducible factor” (www.ncbi.nlm.nih.gov).

IL-22 contains several post-translational features important for its stability and function. It is a glycoprotein with N-linked glycosylation sites at Asn-54 and Asn-97 (experimentally confirmed) and another predicted site at Asn-68 (www.genome.jp). These glycans, also observed in crystal structures, decorate the surface of IL-22 and can influence receptor binding and protein half-life (pmc.ncbi.nlm.nih.gov). IL-22 is further stabilized by two conserved disulfide bonds (Cys-40 to Cys-132, and Cys-89 to Cys-178) that tether its helices together (www.genome.jp) (pmc.ncbi.nlm.nih.gov). These disulfide bridges are critical for maintaining the proper fold of IL-22 as a soluble cytokine. Overall, the domain architecture and cysteine connectivity of IL-22 mirror those of other IL-10 family cytokines, underscoring a preserved structural framework. Notably, structural studies (including X-ray crystallography of human and zebrafish IL-22) have shown IL-22 adopts the typical class-II cytokine architecture, confirming that its 3D structure is highly conserved across species (pubmed.ncbi.nlm.nih.gov).

Biological Processes and Pathways Involvement

IL-22 is deeply involved in innate and adaptive immune processes, especially at mucosal and barrier tissues. As a cytokine primarily acting on epithelial and tissue cells, IL-22 serves as a key mediator of the innate immune response (GO:0045087) and the inflammatory response (GO:0006954) during infection and injury (www.ncbi.nlm.nih.gov). One of its hallmark functions is to promote antimicrobial defense at mucosal surfaces – IL-22 stimulates epithelial cells (in the skin, gut, lung, etc.) to produce antimicrobial peptides (such as β-defensins, S100 proteins, Reg3 lectins in mice) and mucus, thereby strengthening the barrier against pathogenic bacteria and fungi (www.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This activity places IL-22 in the category of cytokines driving defense response to bacterium (GO:0042742) and other microbes as part of the immune system’s first line of defense. For example, IL-22 from Th17 cells or ILC3 cells can induce colon epithelial cells to secrete antibacterial proteins and thus limit bacterial translocation during gut infections (pmc.ncbi.nlm.nih.gov).

In parallel, IL-22 is crucial for tissue repair and regenerative processes. It promotes proliferation and survival of epithelial cells, aiding in wound healing of damaged tissues (www.genecards.org) (www.genome.jp). Upon injury or inflammation, IL-22 signaling helps maintain or restore the integrity of tissue barriers: it encourages epithelial cell growth (GO:0050673) and tissue regeneration (e.g., aiding wound healing, GO:0042060) to fill in damaged areas (www.genecards.org) (pmc.ncbi.nlm.nih.gov). For instance, IL-22 has been shown to drive intestinal stem cell proliferation and epithelial regeneration after acute injury in the gut, largely via STAT3 activation in those cells (www.genecards.org). In the skin, IL-22 causes keratinocytes to hyper-proliferate and migrate, which is helpful for closing wounds (but can contribute to psoriatic pathology when unregulated). In the liver, IL-22 protects hepatocytes from damage and supports their regeneration (as observed in mouse models of liver injury) (pmc.ncbi.nlm.nih.gov). Thus, IL-22 serves a dual role: pro-inflammatory and protective, orchestrating both the immune defense (GO:0006955) against pathogens and the rebuilding of tissue post-damage.

IL-22 often acts in concert with other cytokines and cells. It is a signature effector of the Th17/IL-23 axis: IL-22 production is induced by IL-23 and is typically co-expressed with IL-17A/F in Th17 responses, though IL-22 can also be produced independently by other cell types (pmc.ncbi.nlm.nih.gov). The combined actions of IL-17 and IL-22 are important in conditions like mucosal candidiasis and certain bacterial infections, where IL-17 mobilizes neutrophils and IL-22 fortifies epithelial defenses. In barrier immunity, IL-22’s role is largely protective, helping contain infection and prevent pathogen dissemination (pmc.ncbi.nlm.nih.gov). However, IL-22 can also have pro-inflammatory properties (www.ncbi.nlm.nih.gov) – for example, by sustaining chronic inflammation in autoimmune diseases (discussed below). Importantly, IL-22’s 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. The JAK-STAT pathway (particularly STAT3) is the central pathway triggered by IL-22, linking this cytokine to numerous gene expression programs involved in inflammation, cell survival (e.g. upregulating Bcl-2/Bcl-x_L), and proliferation (www.genome.jp) (www.genecards.org). There is also evidence IL-22 can activate ERK and AKT pathways, meaning it can cross-talk with growth factor signaling to some extent (www.genome.jp). Through these pathways, IL-22 influences a broad set of biological processes, from acute phase responses in the liver (www.genome.jp) to epithelial cell migration (IL-22 was shown to promote epithelial cell spreading and mobility) (www.genome.jp). Overall, IL-22 occupies a unique niche in the immune system: it is an immune mediator that primarily acts on tissues, making it crucial for the crosstalk between the immune system and barrier organ function.

Expression Patterns and Regulation

Cell type expression: IL22 gene expression is normally tightly regulated and is low or undetectable in most resting tissues (www.ncbi.nlm.nih.gov). Under homeostatic conditions, IL-22 mRNA shows a tissue-enhanced pattern predominantly in immune-related sites. RNA profiling indicates highest IL22 expression in lymphoid tissues (such as tonsils, lymph nodes) and in certain barrier organs like the skin and digestive tract, while most other tissues have little to no IL-22 expression (v20.proteinatlas.org). The Human Protein Atlas reports IL22 as “detected in some tissues” with enrichment in lymphoid tissue and urinary bladder (v20.proteinatlas.org). This suggests that IL-22 is not a ubiquitously expressed cytokine but is present in specific contexts – likely produced by immune cells residing in or homing to those tissues.

Cellular sources: The primary producers of IL-22 are activated CD4⁺ T helper cells (notably the Th17 subset, and a related subset sometimes called Th22) and innate lymphoid cells (especially group 3 ILCs, which include lymphoid tissue inducer cells and NK-like cells in mucosal tissues) (pmc.ncbi.nlm.nih.gov). During an immune response, Th17 cells differentiate (under IL-6, TGF-β and IL-1β signals) and, upon stimulation with IL-23, secrete high levels of IL-22 along with IL-17 (pmc.ncbi.nlm.nih.gov). There are also specialized NK-like cells that produce IL-22; for example, NKp46⁺ ILC3 cells in the gut mucosa constitutively express IL-22 or rapidly produce it in response to microbial cues (pmc.ncbi.nlm.nih.gov). In human tonsils and Peyer’s patches, an “NK-22” cell subset (CD56⁺ NK cells) has been described that releases IL-22 when stimulated by IL-23 (pmc.ncbi.nlm.nih.gov). Other cell types that can produce IL-22 include γδ T cells, mucosal-associated invariant T (MAIT) cells, and neutrophils (the latter only under certain inflammatory conditions). Notably, dendritic cells and macrophages do not produce IL-22 – instead, they produce IL-23 and other cytokines that stimulate IL-22 production by lymphocytes.

Inducing signals: The expression of IL22 is induced during inflammatory and infectious conditions. IL-23 is the most potent cytokine for inducing IL-22; it drives IL-22 production from both T cells and ILC3s in the context of infections like bacteria (e.g. Citrobacter rodentium infection in mice triggers an IL-23 → IL-22 axis for gut defense) (pmc.ncbi.nlm.nih.gov). Additionally, pro-inflammatory signals such as IL-1β and TNF-α can synergize to enhance IL-22 output from T cells. Microbial products (via dendritic cells) lead to an IL-23-rich environment, which in turn causes a surge in IL-22 from responding lymphocytes (pmc.ncbi.nlm.nih.gov). This is often seen in mucosal infections: for example, during a bacterial infection at mucosal surfaces, IL-22 gene expression is rapidly upregulated in Th17/ILC3 cells as part of the innate defense mechanism (pmc.ncbi.nlm.nih.gov). Conversely, anti-inflammatory cytokines like IL-10 or regulatory T cells can suppress IL-22 production. The IL22 gene itself is under transcriptional control of factors such as aryl hydrocarbon receptor (AHR) (known to enhance IL-22 in Th17/IL-22-producing cells) and is also influenced by STAT3 (downstream of IL-23 signaling in the IL-22-producing cell).

Regulation and feedback: Because IL-22 can be double-edged, its activity is often counter-regulated. IL-22-producing cells co-express IL-22BP in some contexts: for instance, certain dendritic cells in gut produce IL-22BP to bind IL-22 as a feedback inhibitor. Retinoic acid in the gut environment upregulates IL-22BP, dampening IL-22 to prevent excessive epithelial proliferation. On the other hand, during acute infection, IL-22BP expression is suppressed to allow IL-22 to exert its protective effect. Thus, IL22 expression and action are controlled at multiple levels – transcriptional induction by cytokines (IL-23, etc.), and post-secretory neutralization by IL-22BP. In summary, IL-22 is mainly expressed during immune challenge by specific immune cell subsets, and its production is a hallmark of Th17/ILC3-driven inflammation. Baseline expression in healthy conditions is generally low, highlighting IL-22’s role as an “on-demand” mediator in immunity.

Disease Associations and Phenotypes

Given its role at the interface of immunity and tissue integrity, IL-22 has been implicated in a variety of diseases, especially those involving chronic inflammation or barrier dysfunction. Dysregulated IL-22 – whether excessive or insufficient – can contribute to pathology.

Inflammatory and Autoimmune Diseases: IL-22 is a key effector in several autoimmune or autoinflammatory conditions. High IL-22 levels are found in psoriasis, rheumatoid arthritis, inflammatory bowel disease (IBD) (such as Crohn’s disease and ulcerative colitis), and psoriatic arthritis (pmc.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov). In psoriasis, IL-22 is produced by skin-homing Th17/Th22 cells and drives keratinocyte proliferation and acanthosis (thickening of the epidermis). A mouse study demonstrated that IL-22 is required for Th17-mediated psoriatic skin inflammation – animals lacking IL-22 were protected from developing skin lesions (pmc.ncbi.nlm.nih.gov). This establishes IL-22 as a pathological driver in psoriasis-like disease, making it a potential therapeutic target. In rheumatoid arthritis, IL-22 is elevated in patient sera and synovial fluid and may contribute to joint inflammation and pannus formation (by inducing matrix metalloproteinases and proliferating synovial fibroblasts). In IBD, IL-22 plays a paradoxical role: it is generally protective for the intestinal mucosa (promoting wound healing and mucus production), but overproduction in an inappropriate context could exacerbate inflammation. Indeed, IL-22 is involved in the pathogenesis of several intestinal diseases (www.ncbi.nlm.nih.gov). Elevated IL-22 has been observed in Crohn’s disease lesions, where it correlates with active inflammation; however, IL-22 also helps drive epithelial recovery, suggesting a complex, context-dependent role. Therapeutically, blocking IL-22 has been considered in psoriasis (to reduce keratinocyte overgrowth), whereas recombinant IL-22 or IL-22 fusion proteins have been explored in ulcerative colitis to enhance mucosal healing – highlighting the dual nature of IL-22 in disease.
Chronic Infections and Immune Deficiency: Because IL-22 strengthens barrier defenses, a deficiency in IL-22 can lead to increased susceptibility to infections at barrier sites. For example, patients with HIV or other immunodeficiencies often have reduced IL-22 levels, which is associated with microbial translocation from the gut and skin infections. A notable example is Hidradenitis suppurativa (also known as acne inversa), a chronic inflammatory skin disease: studies have found low IL-22 levels in these patients, and IL-22 deficiency is thought to contribute to the chronic nature of the disease lesions (pubmed.ncbi.nlm.nih.gov). In a 2012 study, HS patients had significantly reduced IL-22-producing T cells, suggesting that insufficient IL-22-mediated repair may permit ongoing inflammation and bacterial persistence in lesions (pubmed.ncbi.nlm.nih.gov). Conversely, excess IL-22 can be problematic in certain infections by fueling inflammation – for instance, in COVID-19, IL-22 is one of the cytokines elevated during the immune response to SARS-CoV-2. IL-22 levels were found to be up-regulated in patients with mild/moderate COVID-19 (pmc.ncbi.nlm.nih.gov) and are part of the complex cytokine milieu in severe cases (though IL-22’s exact role in COVID-19 pathology vs. protection is still under investigation). Given its association with tissue repair, some hypothesize IL-22 might help regenerate lung epithelium after viral injury; indeed, IL-22 is considered a crucial cytokine in host immunity against infections like COVID-19 (www.ncbi.nlm.nih.gov). Research is ongoing to determine if augmenting IL-22 could mitigate lung damage in viral pneumonia or if blocking IL-22 is beneficial in cytokine storm conditions – early data suggest IL-22’s effect in viral disease can be protective in lung tissue recovery, distinguishing it from purely pro-inflammatory cytokines.
Allergy and Asthma: IL-22 has also been linked to allergic inflammation. In diseases like atopic dermatitis (eczema) and asthma, IL-22 is produced by Th22/Th17 cells and can contribute to barrier dysfunction. In atopic dermatitis, IL-22 is highly expressed in lesions and correlates with epidermal hyperplasia and impaired differentiation (leading to a defective skin barrier). Targeting IL-22 in such conditions (e.g., with IL-22 neutralizing antibodies) is being explored to restore normal barrier function.
Cancer: IL-22’s ability to promote cell survival and proliferation ties it to cancer development in chronically inflamed tissues. IL-22 is overexpressed in several cancers, especially those arising from epithelial cells in the context of inflammation. For example, colorectal cancer arising from IBD-affected colon may be accelerated by IL-22, as IL-22 creates a proliferative, pro-survival environment for preneoplastic cells. In the liver, chronically elevated IL-22 (due to hepatitis or fatty liver inflammation) can contribute to hepatocellular carcinoma (HCC) by continually stimulating hepatocyte survival and proliferation – although IL-22 also induces acute phase reactants, the mitogenic effect on hepatocytes in a dysregulated environment may favor tumorigenesis (pmc.ncbi.nlm.nih.gov). A recent study highlighted the IL-22–IL-22BP axis in HCC: low levels of the decoy IL-22BP (meaning unopposed IL-22 signaling) were associated with tumor progression, suggesting IL-22 promotes liver tumor cell growth when not properly restrained (pubmed.ncbi.nlm.nih.gov). Additionally, IL-22 receptors are expressed on some cancer cells; for example, glioblastoma cells have been shown to express IL-22RA1 and respond to IL-22 by activating STAT3, which enhances their survival and resistance to apoptosis (www.genome.jp). This finding (from a 2015 study) indicates that tumors can co-opt the IL-22/STAT3 pathway to support malignant cell survival, linking IL-22 to cancer cell-intrinsic signaling. Other cancers where IL-22 is implicated include gastric cancer (often linked with IL-22 from tumor-infiltrating lymphocytes), lung cancer (IL-22 can be elevated in smokers and in COPD-related lung tumors), and pancreatic cancer. However, IL-22’s role can vary – in some contexts it might help tissue integrity and prevent dysplasia (as in acute colitis), whereas in established tumors it usually appears to favor tumor growth or immune evasion (through tissue repair mechanisms that also shield tumor cells).
Ophthalmologic and Other Conditions: Gene association studies have linked IL22 to conditions like scleritis (inflammatory disease of the eye sclera) (www.genecards.org), where IL-22 may contribute to the local immune response and tissue damage. IL22 gene polymorphisms have been examined in diseases such as type 1 diabetes, systemic lupus erythematosus, and atherosclerosis, although findings are not always consistent. In summary, IL-22 is broadly involved in diseases characterized by epithelial barrier disruption and chronic inflammation, and it can be either pathogenic or protective depending on the context. Its unique dual nature makes it an attractive yet challenging target for therapeutic intervention.

Evolutionary Conservation

IL-22 is highly conserved across vertebrate species, reflecting its fundamental role in immune defense of barrier tissues. Genes orthologous to human IL22 have been identified in mammals, birds, and even lower vertebrates such as amphibians and fish (pubmed.ncbi.nlm.nih.gov). In fact, teleost fish possess an IL-22 homolog and the requisite IL-22 receptor components (IL-22RA1, IL-10R2) and an IL-22BP, indicating that the IL-22 signaling system was already in place early in vertebrate evolution (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). The IL-22 protein sequence is moderately conserved – for example, human IL-22 shares roughly ~70–80% amino acid identity with mouse IL-22, and key cysteine residues and functional motifs are preserved. This conservation extends to structure: the 3D structure of zebrafish IL-22 has been solved and is highly similar to that of human IL-22, displaying the same 6-helix bundle fold and disulfide bond pattern (pubmed.ncbi.nlm.nih.gov). Such structural conservation despite sequence divergence (teleost IL-22 diverges in sequence but retains the fold) underscores the strong evolutionary pressure to maintain IL-22’s function. Phylogenetic analysis suggests that IL-22 (and the closely related IL-26) arose early in the evolution of the IL-10 family cytokine cluster (pubmed.ncbi.nlm.nih.gov). IL-22 and IL-26 likely split off as a distinct branch after IL-10, meaning the ability to signal to epithelial cells via IL-22RA1 is an ancient adaptation in the immune system. No IL-22 homologs are found in invertebrates (since the class II cytokine family is vertebrate-specific), emphasizing that IL-22’s emergence aligns with the development of adaptive immunity and sophisticated barrier defense mechanisms in vertebrates. Even among mammals, IL-22’s sequence is quite conserved – human IL-22 can cross-react with some other species’ receptors (e.g., human IL-22 is active on mouse cells that express the IL-22 receptor, albeit with different affinity), which is why in vivo mouse models using human IL-22 or vice versa have been partially successful. This cross-species activity further illustrates conserved receptor-ligand interactions. Overall, the IL22 gene exemplifies how important barrier immunity cytokines have been preserved through evolution to protect organisms against environmental microbes while maintaining tissue homeostasis.

Key Experimental Evidence and Landmark Studies

Discovery of IL-22 (2000): IL-22 was first identified around 2000 by two independent groups. Dumoutier et al. cloned a novel IL-10-related gene induced in T cells, originally named IL-TIF (IL-10-related T-cell Inducible Factor) (www.genome.jp). They showed IL-TIF/IL-22 could act on hepatoma cells to induce acute phase proteins, suggesting a role in liver inflammation and the acute phase response (www.genome.jp). Around the same time, Xie et al. reported a novel cytokine (which turned out to be the same IL-22) that signals through components of the class II cytokine receptor family (www.genome.jp). This study demonstrated that IL-22 utilizes the IL-22R1 (at that time called “CRF2-9”) and IL-10R2 (“CRF2-4”) receptor subunits, distinct from IL-10 which uses IL-10R1/IL-10R2 (www.genome.jp). These early findings established IL-22 as a member of the IL-10 family with unique target-cell specificity (hepatocytes, epithelial cells) and receptor usage.
Structure-function analyses: Several structural biology studies have been pivotal in understanding IL-22. In 2005, Xu et al. solved the crystal structure of IL-22 at 2.6 Å resolution, revealing the six α-helix bundle monomer and confirming the two disulfide bonds and glycosylation sites (www.genome.jp). Later, in 2008, Jones et al. solved the co-crystal structure of IL-22 bound to its high-affinity receptor IL-22RA1 (www.genome.jp). This provided insight into the IL-22/receptor interface, mapping key binding residues on IL-22 and showing how IL-22RA1 engages one face of the IL-22 molecule while IL-10R2 would bind another region. Interestingly, these studies noted IL-22 remains monomeric in solution (unlike IL-10 which is a tight dimer) (pmc.ncbi.nlm.nih.gov), explaining why IL-22 functions independently. The structural data also explained the necessity of IL-22’s N-linked glycans for receptor binding – one study observed that glycosylation (particularly at Asn54 in helix A) can affect IL-22’s affinity for IL-22R1 (pmc.ncbi.nlm.nih.gov). These foundational structure-function works guide current efforts to engineer IL-22 mutants or design blocking antibodies (like those that prevent IL-22 from binding IL-22RA1).
Role in inflammatory disease models: Numerous animal model studies have elucidated IL-22’s functions:
Pathogenic role in skin inflammation: Boniface et al. (2005) and Zheng et al. (2007) first noted high IL-22 in psoriasis patients. Then, a 2008 JCI study by Zheng et al. used IL-22 knockout mice to show that IL-22 is required for IL-23/Th17-mediated psoriasis-like skin changes (pmc.ncbi.nlm.nih.gov). Mice lacking IL-22 were resistant to the epidermal thickening and cytokine expression induced by IL-23, firmly establishing IL-22 as a driver of psoriatic pathology. This study is often cited as evidence for IL-22’s Th17-dependent pro-inflammatory role.
Protective role in liver injury: A 2004 study by Radaeva et al. in Hepatology demonstrated that IL-22 protected mice from concanavalin A-induced hepatitis. They found IL-22 acts as a survival factor for hepatocytes via STAT3 activation, reducing liver damage (pmc.ncbi.nlm.nih.gov). In vitro, IL-22 could prevent hepatocyte apoptosis. This highlighted IL-22’s therapeutic potential in liver diseases and led to the concept that IL-22 is generally hepatoprotective (which later studies in alcoholic liver disease and ischemia-reperfusion injury corroborated).
Mucosal infection and IL-22BP: In 2011, Zenewicz et al. reported that IL-22BP (the IL-22 inhibitor) regulated IL-22 during intestinal infection by Citrobacter, and deletion of IL-22BP allowed more effective clearance of bacteria due to enhanced IL-22 activity. Conversely, excess IL-22BP worsened infection outcomes (pubmed.ncbi.nlm.nih.gov). Complementary work by Kim et al. (2011) showed IL-22⁻/⁻ mice were highly susceptible to Citrobacter infection, but administration of IL-22-Fc protein could rescue them. Together these demonstrate IL-22 is a critical anti-microbial cytokine in gut infection, and its regulation by IL-22BP is biologically important.
IL-22 in lung and viral infections: Recent studies (2020–2022) have examined IL-22 in influenza and COVID-19 models. For instance, therapeutic IL-22 has shown promise in preclinical models of influenza-induced lung injury, helping to regenerate airway epithelium. In the context of COVID-19, some researchers have proposed using IL-22 or IL-22 agonists to rebuild lung tissue post-infection (pmc.ncbi.nlm.nih.gov) (based on IL-22’s known role in lung epithelial repair). These avenues are still in experimental stages, but they underscore the translational interest in IL-22.
Clinical correlations: Elevated IL-22 levels have been observed in patients with diseases like psoriasis, atopic dermatitis, rheumatoid arthritis, IBD, COPD, and even cancer (e.g. IL-22 is found in the tumor microenvironment of colon and liver cancers) (www.genecards.org) (www.genome.jp). Clinical trials are underway targeting the IL-22 pathway: for example, an IL-22 neutralizing antibody (fezakinumab) was tested in atopic dermatitis and showed some improvement in skin lesions. Conversely, an IL-22 agonist (F-652, a recombinant IL-22 dimer) has been tested in alcoholic hepatitis to promote liver regeneration with some positive signals. These studies are informed by the foundational research outlined above and could pave the way for IL-22–targeted therapies in inflammatory diseases.

In conclusion, IL-22 is a multifaceted cytokine with crucial roles in mucosal immunity, inflammation, and tissue homeostasis. Its gene and protein have been well-characterized in terms of sequence, structure, and function, providing a solid basis for Gene Ontology annotation. IL-22 exhibits cytokine activity and interleukin-22 receptor binding functions (www.genecards.org), operates in the extracellular region after secretion (www.proteinatlas.org), and participates in key biological processes such as inflammatory response, innate immune response, defense response to bacteria, epithelial cell proliferation, and tissue regeneration (www.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The rich literature spanning from molecular structure to animal models and human disease associations makes IL-22 an important gene for curated annotation in the context of immune and epithelial biology.

Relevant Gene Ontology (GO) Terms

Molecular Function: Cytokine activity (GO:0005125) – IL-22 functions as a soluble signaling molecule that binds receptors on target cells (www.genecards.org). Interleukin-22 receptor binding (GO:0045518) – IL-22 specifically binds the IL-22RA1/IL-10RB receptor complex on cell surfaces (www.genecards.org).
Cellular Component: Extracellular region (GO:0005576) – IL-22 is located outside the cell, in the extracellular space/secreted milieu, where it can diffuse and reach receptors on other cells (www.proteinatlas.org). (As a secreted cytokine, IL-22 is not associated with intracellular compartments.)
Biological Process: Inflammatory response (GO:0006954) – IL-22 is involved in mediating and modulating inflammation, often through inducing acute phase proteins and inflammatory mediators in tissues (www.ncbi.nlm.nih.gov). Innate immune response (GO:0045087) – IL-22 plays a role in the body’s initial defense, particularly at epithelial barriers, by enhancing innate immune functions like antimicrobial peptide release (pmc.ncbi.nlm.nih.gov). Defense response to bacterium (GO:0042742) – IL-22 contributes to protecting mucosal surfaces from bacterial infection by strengthening barrier defenses and microbial killing (www.ncbi.nlm.nih.gov). Epithelial cell proliferation (GO:0050673) – IL-22 promotes the growth and proliferation of epithelial cells, aiding tissue recovery (for example, in skin or gut epithelia) (www.genecards.org). Tissue regeneration (GO:0031100) – IL-22 is involved in regenerating damaged tissues and maintaining epithelial integrity after injury (www.genecards.org). These processes align with IL-22’s observed functions in wound healing, mucosal repair, and recovery from inflammation. Each of the above GO terms is supported by experimental evidence in the literature, making IL-22 a well-annotated gene in the context of immune and epithelial biology.

📄 View Raw YAML

---
id: Q9GZX6
gene_symbol: IL22
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
existing_annotations:
  - term:
      id: GO:0005125
      label: cytokine activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:10875937
          supporting_text: 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.
        - reference_id: PMID:10954742
          supporting_text: 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.
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IL-22 is definitively localized to the extracellular space as a secreted
        cytokine. The protein contains a signal peptide (aa 1-33) that directs it
        through the secretory pathway, and mature IL-22 functions in the extracellular
        environment where it binds to receptors on target cells. The IBA annotation
        is well-supported by phylogenetic conservation.
      action: ACCEPT
      reason: IL-22 is a secreted protein that functions in the extracellular space.
        Multiple structural and functional studies confirm its extracellular localization,
        including crystal structures of IL-22 bound to its receptor and functional
        assays showing it acts on cell surface receptors. This is a core aspect of
        IL-22 biology.
      supported_by:
        - reference_id: file:human/IL22/IL22-uniprot.txt
          supporting_text: 'Subcellular location: Secreted. [Signal peptide prediction
            based on analysis of experimentally verified cleavage sites - PROTEIN
            SEQUENCE OF 34-48]'
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: IL-22 is a secreted protein. It contains an N-terminal
            signal peptide (amino acids 1–33) that directs it into the endoplasmic
            reticulum/Golgi secretory pathway, after which the mature cytokine is
            released into the extracellular space.
  - term:
      id: GO:0050728
      label: negative regulation of inflammatory response
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: MODIFY
      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.
      proposed_replacement_terms:
        - id: GO:0050727
          label: regulation of inflammatory response
        - id: GO:0032103
          label: positive regulation of response to external stimulus
      supported_by:
        - reference_id: PMID:10875937
          supporting_text: 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
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: 'IL-22 can also have pro-inflammatory properties – for
            example, by sustaining chronic inflammation in autoimmune diseases...
            IL-22 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.'
  - term:
      id: GO:0007165
      label: signal transduction
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: Signal transduction is too general a term for IL-22. While IL-22 does
        activate signal transduction pathways (JAK-STAT, MAPK, PI3K/AKT) in target
        cells, this annotation lacks specificity. More precise terms describing IL-22
        receptor binding or cytokine-mediated signaling would be more informative.
      action: MODIFY
      reason: This overly broad term provides little functional information. IL-22
        specifically activates JAK-STAT signaling through its receptor complex. More
        specific annotations like "cytokine-mediated signaling pathway" (GO:0019221)
        or "JAK-STAT cascade" (GO:0007259) would be more appropriate.
      proposed_replacement_terms:
        - id: GO:0019221
          label: cytokine-mediated signaling pathway
        - id: GO:0007259
          label: cell surface receptor signaling pathway via JAK-STAT
      supported_by:
        - reference_id: PMID:10875937
          supporting_text: Cell lines were identified that respond to IL-22 by activation
            of STATs 1, 3, and 5
        - reference_id: PMID:10954742
          supporting_text: Recombinant human IL-TIF was found to activate signal transducer
            and activator of transcription factors-1 and -3 in several hepatoma cell
            lines.
  - term:
      id: GO:0005125
      label: cytokine activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: file:human/IL22/IL22-uniprot.txt
          supporting_text: 'RecName: Full=Interleukin-22; Short=IL-22; AltName: Full=Cytokine
            Zcyto18'
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Correct localization annotation. IL-22 functions in the extracellular
        region as a secreted cytokine. This broader term (extracellular region) is
        appropriate alongside the more specific extracellular space annotation.
      action: ACCEPT
      reason: IL-22 is correctly annotated to the extracellular region. As a secreted
        cytokine, it functions outside cells in the extracellular environment. This
        annotation is consistent with experimental evidence and complements the more
        specific extracellular space annotation.
      supported_by:
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: Consequently, the functional location of IL-22 is the extracellular
            region, where it diffuses to interact with receptors on target cell surfaces.
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Duplicate annotation of extracellular space localization via automated
        methods. While correct, this duplicates the IBA annotation which has stronger
        phylogenetic support.
      action: ACCEPT
      reason: Correct annotation supported by multiple lines of evidence. IL-22 is
        a secreted protein that functions in the extracellular space. Multiple evidence
        codes for the same correct annotation provide complementary support.
      supported_by:
        - reference_id: file:human/IL22/IL22-uniprot.txt
          supporting_text: 'Subcellular location: Secreted.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12513909
    review:
      summary: Generic protein binding annotation that provides minimal functional
        information. IL-22 specifically binds IL-22R1 and IL-10RB receptors. This
        should be replaced with the more specific "interleukin-22 receptor binding"
        term.
      action: MODIFY
      reason: While IL-22 does bind proteins (its receptors), the generic "protein
        binding" term is uninformative. The specific annotation "interleukin-22 receptor
        binding" (GO:0045518) or "cytokine receptor binding" (GO:0005126) would be
        more appropriate and informative.
      proposed_replacement_terms:
        - id: GO:0045518
          label: interleukin-22 receptor binding
        - id: GO:0005126
          label: cytokine receptor binding
      supported_by:
        - reference_id: PMID:12513909
          supporting_text: Comparison of interleukin-22 and interleukin-10 soluble
            receptor complexes
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18599299
    review:
      summary: Generic protein binding annotation from structural study of IL-22/IL-22R1
        complex. Should be replaced with specific receptor binding annotation.
      action: MODIFY
      reason: This paper specifically describes the crystal structure of IL-22 bound
        to IL-22R1, demonstrating specific receptor binding rather than generic protein
        binding. The annotation should use "interleukin-22 receptor binding" (GO:0045518).
      proposed_replacement_terms:
        - id: GO:0045518
          label: interleukin-22 receptor binding
      additional_reference_ids: ["PMID:18599299"]
      supported_by:
        - reference_id: PMID:18599299
          supporting_text: Structure of IL-22 bound to its high-affinity IL-22R1 chain
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18675809
    review:
      summary: Another generic protein binding annotation from IL-22/IL-22R1 structural
        study. Should specify receptor binding.
      action: MODIFY
      reason: This paper describes the crystal structure of the IL-22/IL-22R1 complex
        and signaling mechanism, demonstrating specific receptor binding. Should use
        "interleukin-22 receptor binding" (GO:0045518) instead of generic protein
        binding.
      proposed_replacement_terms:
        - id: GO:0045518
          label: interleukin-22 receptor binding
      additional_reference_ids: ["PMID:18675809"]
      supported_by:
        - reference_id: PMID:18675809
          supporting_text: Crystal structure of the IL-22/IL-22R1 complex and its
            implications for the IL-22 signaling mechanism
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20462497
    review:
      summary: Generic protein binding annotation describing IL-10RB interaction.
        Should specify receptor binding activity.
      action: MODIFY
      reason: This paper describes receptor sharing by IL-10R2 (IL-10RB), which is
        part of the IL-22 receptor complex. The annotation should specify "interleukin-22
        receptor binding" or "cytokine receptor binding" rather than generic protein
        binding.
      proposed_replacement_terms:
        - id: GO:0045518
          label: interleukin-22 receptor binding
        - id: GO:0005126
          label: cytokine receptor binding
      additional_reference_ids: ["PMID:20462497"]
      supported_by:
        - reference_id: PMID:20462497
          supporting_text: Structure and mechanism of receptor sharing by the IL-10R2
            common chain
  - term:
      id: GO:0051384
      label: response to glucocorticoid
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: anti-inflammatory cytokines like IL-10 or regulatory T
            cells can suppress IL-22 production [glucocorticoids act similarly as
            anti-inflammatory agents]
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-448480
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: Reactome:R-HSA-448480
          supporting_text: IL22 binds IL22RA1:JAK1 receptor complex [occurs in extracellular
            region]
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-448741
    review:
      summary: Correct annotation showing IL-22 binding to its soluble antagonist
        IL-22RA2 (IL-22BP) in the extracellular region.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:11481447
          supporting_text: We demonstrate that IL-22RA2 binds specifically to IL-22
            and neutralizes IL-22-induced proliferation
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8854645
    review:
      summary: Another correct Reactome annotation showing IL-22 receptor complex
        formation in the extracellular region.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: Reactome:R-HSA-8854645
          supporting_text: IL22:IL22RA1:JAK1 binds IL10RB:TYK2
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8986995
    review:
      summary: Correct Reactome annotation documenting IL-22 signaling pathway events
        in the extracellular region.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: Consistent with this, Reactome and other pathway databases
            localize IL-22 to the extracellular region in human pathways.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8987014
    review:
      summary: Correct Reactome annotation documenting IL-22 signaling pathway events
        in the extracellular region.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: Consistent with this, Reactome and other pathway databases
            localize IL-22 to the extracellular region in human pathways.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8987042
    review:
      summary: Correct Reactome annotation documenting IL-22 signaling pathway events
        in the extracellular region.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: Consistent with this, Reactome and other pathway databases
            localize IL-22 to the extracellular region in human pathways.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8987070
    review:
      summary: Correct Reactome annotation documenting IL-22 signaling pathway events
        in the extracellular region.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: Consistent with this, Reactome and other pathway databases
            localize IL-22 to the extracellular region in human pathways.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8987132
    review:
      summary: Correct Reactome annotation documenting IL-22 signaling pathway events
        in the extracellular region.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: Consistent with this, Reactome and other pathway databases
            localize IL-22 to the extracellular region in human pathways.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8987236
    review:
      summary: Correct Reactome annotation documenting IL-22 signaling pathway events
        in the extracellular region.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: Consistent with this, Reactome and other pathway databases
            localize IL-22 to the extracellular region in human pathways.
  - term:
      id: GO:0006953
      label: acute-phase response
    evidence_type: NAS
    original_reference_id: PMID:11481447
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:10954742
          supporting_text: 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.
        - reference_id: PMID:11481447
          supporting_text: 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.
  - term:
      id: GO:0006954
      label: inflammatory response
    evidence_type: NAS
    original_reference_id: PMID:10954742
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:10954742
          supporting_text: IL-TIF expression was found to be rapidly increased after
            lipopolysaccharide (LPS) injection, suggesting that this cytokine contributes
            to the inflammatory response in vivo.
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: IL-22 serves as a key mediator of the innate immune response
            (GO:0045087) and the inflammatory response (GO:0006954) during infection
            and injury.
  - term:
      id: GO:0045518
      label: interleukin-22 receptor binding
    evidence_type: NAS
    original_reference_id: PMID:10875937
    review:
      summary: IL-22 specifically binds to the IL-22 receptor complex composed of
        IL-22R1 (IL-22RA1) and IL-10RB (IL-10R2). This is a core molecular function
        that has been extensively characterized through structural and biochemical
        studies.
      action: ACCEPT
      reason: Interleukin-22 receptor binding is a defining molecular function of
        IL-22. The protein binds with high affinity to IL-22R1 and forms a signaling
        complex with IL-10RB. This specific receptor binding activity distinguishes
        IL-22 from other IL-10 family members and is essential for all IL-22 biological
        functions.
      supported_by:
        - reference_id: PMID:10875937
          supporting_text: 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.
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: IL-22 binds to a heterodimeric receptor complex composed
            of IL-22RA1 (a cell-type specific α-chain on epithelial and stromal cells)
            and the shared IL-10RB (IL-10R2) β-chain.
  - term:
      id: GO:0050832
      label: defense response to fungus
    evidence_type: IC
    original_reference_id: file:human/IL22/IL22-deep-research.md
    review:
      summary: IL-22 mediates defense responses against fungal pathogens at barrier
        surfaces by inducing antimicrobial peptides. This function is directly stated
        in the deep research but not currently annotated.
      action: NEW
      reason: IL-22 plays a documented role in antifungal defense through antimicrobial
        peptide induction. The deep research explicitly states IL-22 strengthens barriers
        against both bacteria AND fungi, but only bacterial defense is currently annotated.
      supported_by:
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: IL-22 stimulates epithelial cells (in the skin, gut, lung,
            etc.) to produce antimicrobial peptides (such as β-defensins, S100 proteins,
            Reg3 lectins in mice) and mucus, thereby strengthening the barrier against
            pathogenic bacteria and fungi
  - term:
      id: GO:0010631
      label: epithelial cell migration
    evidence_type: IC
    original_reference_id: file:human/IL22/IL22-deep-research.md
    review:
      summary: IL-22 promotes epithelial cell migration and spreading, which is important
        for wound healing and tissue repair. This is a direct effect of IL-22 signaling.
      action: NEW
      reason: IL-22 directly promotes epithelial cell migration through its signaling
        pathways. This is distinct from proliferation and is an important component
        of wound healing.
      supported_by:
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: epithelial cell migration (IL-22 was shown to promote epithelial
            cell spreading and mobility)
  - term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    evidence_type: IC
    original_reference_id: file:human/IL22/IL22-deep-research.md
    review:
      summary: IL-22 promotes cell survival and protects cells from apoptosis, particularly
        in hepatocytes and epithelial cells. This anti-apoptotic effect is mediated
        through STAT3 activation and upregulation of survival proteins.
      action: NEW
      reason: Cell survival/anti-apoptosis is a core function of IL-22, particularly
        important for its tissue-protective effects. Multiple studies demonstrate
        IL-22 prevents apoptosis in target cells.
      supported_by:
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: These signaling cascades promote target cell survival,
            proliferation, and repair, enabling tissues to withstand and recover from
            inflammatory damage
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: IL-22 acts as a survival factor for hepatocytes via STAT3
            activation, reducing liver damage... In vitro, IL-22 could prevent hepatocyte
            apoptosis
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: linking this cytokine to numerous gene expression programs
            involved in inflammation, cell survival (e.g. upregulating Bcl-2/Bcl-x_L)
  - term:
      id: GO:0070257
      label: positive regulation of mucus secretion
    evidence_type: IC
    original_reference_id: file:human/IL22/IL22-deep-research.md
    review:
      summary: IL-22 stimulates mucus production by epithelial cells at barrier surfaces,
        which is an important component of antimicrobial defense and barrier function.
      action: NEW
      reason: Mucus production is specifically mentioned as an IL-22-induced protective
        mechanism at mucosal barriers. This is distinct from antimicrobial peptide
        production and represents an important barrier defense function.
      supported_by:
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: IL-22 stimulates epithelial cells (in the skin, gut, lung,
            etc.) to produce antimicrobial peptides (such as β-defensins, S100 proteins,
            Reg3 lectins in mice) and mucus, thereby strengthening the barrier against
            pathogenic bacteria and fungi
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: 'IL-22 plays a paradoxical role: it is generally protective
            for the intestinal mucosa (promoting wound healing and mucus production)'
  - term:
      id: GO:0072089
      label: stem cell proliferation
    evidence_type: IC
    original_reference_id: file:human/IL22/IL22-deep-research.md
    review:
      summary: IL-22 promotes intestinal stem cell proliferation, which is crucial
        for epithelial regeneration after injury. This is a specific and important
        function distinct from general epithelial proliferation.
      action: NEW
      reason: IL-22 specifically drives stem cell proliferation in the intestine,
        which is mechanistically distinct from differentiated epithelial cell proliferation.
        This function is key to IL-22s regenerative capacity.
      supported_by:
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: IL-22 has been shown to drive intestinal stem cell proliferation
            and epithelial regeneration after acute injury in the gut, largely via
            STAT3 activation in those cells
  - term:
      id: GO:0002225
      label: positive regulation of antimicrobial peptide production
    evidence_type: IEA
    review:
      summary: IL-22 stimulates epithelial cells to produce antimicrobial peptides
        such as β-defensins, S100 proteins, and Reg3 lectins at mucosal surfaces as
        part of barrier defense
      action: NEW
      reason: This is a hallmark function of IL-22 at mucosal surfaces, where it strengthens
        epithelial barriers by inducing antimicrobial peptide production in skin,
        gut, and lung epithelial cells
      supported_by:
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: IL-22 stimulates epithelial cells (in the skin, gut, lung,
            etc.) to produce antimicrobial peptides (such as β-defensins, S100 proteins,
            Reg3 lectins in mice) and mucus, thereby strengthening the barrier against
            pathogenic bacteria and fungi
  - term:
      id: GO:0042060
      label: wound healing
    evidence_type: IEA
    review:
      summary: IL-22 promotes epithelial regeneration for wound healing
      action: NEW
      reason: IL-22 plays an essential role in regenerating epithelial cells after
        injury to maintain barrier function and prevent further tissue damage. It
        induces proliferation and antimicrobial peptide production in keratinocytes
        and intestinal epithelial cells.
      supported_by:
        - reference_id: PMID:17204547
          supporting_text: IL-22-mediated liver cell regeneration
  - term:
      id: GO:0042742
      label: defense response to bacterium
    evidence_type: IEA
    review:
      summary: IL-22 induces antimicrobial peptides for bacterial defense
      action: NEW
      reason: IL-22 induces production of antimicrobial peptides (β-defensins, S100
        proteins, RegIIIγ) in epithelial cells at mucosal surfaces. This provides
        critical defense against bacterial pathogens at barrier sites like intestine
        and lung.
      supported_by:
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: IL-22 induces antimicrobial peptide production
  - term:
      id: GO:0045087
      label: innate immune response
    evidence_type: IEA
    review:
      summary: IL-22 mediates innate immunity at epithelial barriers
      action: NEW
      reason: IL-22 is a key mediator of innate immunity at epithelial surfaces, inducing
        antimicrobial peptide production and maintaining barrier integrity. Unlike
        other cytokines, IL-22 acts on tissue cells rather than immune cells to coordinate
        innate defense.
      supported_by:
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: IL-22 targets epithelial cells rather than immune cells
  - term:
      id: GO:0050673
      label: epithelial cell proliferation
    evidence_type: IEA
    review:
      summary: IL-22 induces epithelial cell proliferation for tissue repair
      action: NEW
      reason: IL-22 directly stimulates proliferation of epithelial cells including
        keratinocytes, intestinal epithelial cells, and hepatocytes. This proliferative
        response is essential for tissue regeneration and barrier restoration after
        injury.
      supported_by:
        - reference_id: PMID:17204547
          supporting_text: IL-22-mediated liver cell regeneration
  - term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    evidence_type: IEA
    review:
      summary: IL-22 binding to its heterodimeric receptor (IL-22RA1/IL-10RB) activates
        JAK1 and TYK2 tyrosine kinases, leading to STAT3 phosphorylation and downstream
        signaling
      action: NEW
      reason: The JAK-STAT pathway (particularly STAT3) is the central and primary
        signaling mechanism triggered by IL-22 upon receptor binding, essential for
        all IL-22 functions
      supported_by:
        - reference_id: file:human/IL22/IL22-deep-research.md
          supporting_text: Upon ligand binding, this receptor activates the JAK1 and
            TYK2 tyrosine kinases, leading to phosphorylation of STAT3 and downstream
            signaling via the ERK, PI3K/AKT, and STAT3 pathways. The JAK-STAT pathway
            (particularly STAT3) is the central pathway triggered by IL-22
core_functions:
  - description: Interleukin-22 receptor binding activates JAK-STAT signaling in epithelial
      cells to induce antimicrobial peptide production
    molecular_function:
      id: GO:0045518
      label: interleukin-22 receptor binding
    directly_involved_in:
      - id: GO:0002225
        label: positive regulation of antimicrobial peptide production
      - id: GO:0042742
        label: defense response to bacterium
      - id: GO:0007259
        label: cell surface receptor signaling pathway via JAK-STAT
    locations:
      - id: GO:0005576
        label: extracellular region
    supported_by:
      - reference_id: file:human/IL22/IL22-deep-research.md
        supporting_text: IL-22 stimulates epithelial cells (in the skin, gut, lung,
          etc.) to produce antimicrobial peptides (such as β-defensins, S100 proteins,
          Reg3 lectins in mice) and mucus, thereby strengthening the barrier against
          pathogenic bacteria and fungi
      - reference_id: PMID:10875937
        supporting_text: Cell lines were identified that respond to IL-22 by activation
          of STATs 1, 3, and 5
  - description: Cytokine activity stimulates hepatocyte acute phase protein synthesis
      through STAT3 activation
    molecular_function:
      id: GO:0005125
      label: cytokine activity
    directly_involved_in:
      - id: GO:0006953
        label: acute-phase response
      - id: GO:0006954
        label: inflammatory response
    locations:
      - id: GO:0005576
        label: extracellular region
  - description: Interleukin-22 receptor binding promotes epithelial cell proliferation
      and tissue repair at barrier surfaces
    molecular_function:
      id: GO:0045518
      label: interleukin-22 receptor binding
    directly_involved_in:
      - id: GO:0050673
        label: epithelial cell proliferation
      - id: GO:0042060
        label: wound healing
      - id: GO:0045087
        label: innate immune response
    locations:
      - id: GO:0005576
        label: extracellular region
    supported_by:
      - reference_id: file:human/IL22/IL22-deep-research.md
        supporting_text: IL-22 promotes proliferation and survival of epithelial cells,
          aiding in wound healing of damaged tissues... IL-22 has been shown to drive
          intestinal stem cell proliferation and epithelial regeneration after acute
          injury in the gut, largely via STAT3 activation
references:
  - 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:0000108
    title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
      links.
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods.
    findings: []
  - id: PMID:10875937
    title: Interleukin (IL)-22, a novel human cytokine that signals through the interferon
      receptor-related proteins CRF2-4 and IL-22R.
    findings: []
  - id: PMID:10954742
    title: 'Human interleukin-10-related T cell-derived inducible factor: molecular
      cloning and functional characterization as an hepatocyte-stimulating factor.'
    findings: []
  - id: PMID:11481447
    title: A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring
      IL-22 antagonist.
    findings: []
  - id: PMID:12513909
    title: Comparison of interleukin-22 and interleukin-10 soluble receptor complexes.
    findings: []
  - id: PMID:18599299
    title: Structure of IL-22 bound to its high-affinity IL-22R1 chain.
    findings: []
  - id: PMID:18675809
    title: Crystal structure of the IL-22/IL-22R1 complex and its implications for
      the IL-22 signaling mechanism.
    findings: []
  - id: PMID:20462497
    title: Structure and mechanism of receptor sharing by the IL-10R2 common chain.
    findings: []
  - id: Reactome:R-HSA-448480
    title: IL22 binds IL22RA1:JAK1 receptor complex
    findings: []
  - id: Reactome:R-HSA-448741
    title: IL22RA2 binds IL22
    findings: []
  - id: Reactome:R-HSA-8854645
    title: IL22:IL22RA1:JAK1 binds IL10RB:TYK2
    findings: []
  - id: Reactome:R-HSA-8986995
    title: IL22:IL22RA1:p-JAK1:IL10RB:p-TYK2 phosphorylates IL22RA
    findings: []
  - id: Reactome:R-HSA-8987014
    title: IL22:p-Y251,p-Y301-IL22RA1:p-JAK1:PTPN11:IL10RB:p-TYK2 binds STAT3
    findings: []
  - id: Reactome:R-HSA-8987042
    title: IL22:IL22RA1:JAK1:IL10RB:TYK2 phosphorylates JAK1,TYK2
    findings: []
  - id: Reactome:R-HSA-8987070
    title: IL22:p-Y251,p-Y301-IL22RA1:p-JAK1:IL10RB:p-TYK2:STAT3 phosphorylates STAT3
    findings: []
  - id: Reactome:R-HSA-8987132
    title: IL22:p‑Y251,p‑Y301‑IL22RA1:p‑JAK1:PTPN11:IL10RB:p‑TYK2 binds PTPN11
    findings: []
  - id: Reactome:R-HSA-8987236
    title: p-Y705-STAT3 dissociates from IL22:p-Y251,p-Y301-IL22RA1:p-JAK1:IL10RB:p-TYK2:p-Y705-STAT3
    findings: []
  - id: file:human/IL22/IL22-deep-research.md
    title: IL22 Deep Research Report (AI-generated synthesis)
    findings: []
status: COMPLETE

IL22

Gene Description

Existing Annotations Review

Core Functions

Interleukin-22 receptor binding activates JAK-STAT signaling in epithelial cells to induce antimicrobial peptide production

Cytokine activity stimulates hepatocyte acute phase protein synthesis through STAT3 activation

Interleukin-22 receptor binding promotes epithelial cell proliferation and tissue repair at barrier surfaces

References

Deep Research

Falcon

Citations

Deep Research Report: IL22 (human)

Deep Research Report: IL22 (human)

IL22 (Human Interleukin-22) – Comprehensive Gene Report

Gene Function and Molecular Mechanisms

Cellular Localization and Structure

Biological Processes and Pathways Involvement

Expression Patterns and Regulation

Disease Associations and Phenotypes

Evolutionary Conservation

Key Experimental Evidence and Landmark Studies

Relevant Gene Ontology (GO) Terms

📄 View Raw YAML

🔗 Related Resources