IL13

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0002639 positive regulation of immunoglobulin production	IBA GO_REF:0000033	ACCEPT	Summary: IL-13 cooperates with IL-4 and CD40 signaling to promote immunoglobulin class switching, particularly IgE and IgG4 production, in B cells. This is a well-established core function of IL-13 supported by multiple primary studies (PMID:7903680, PMID:8096327) and reviews. Reason: IBA annotation is well-supported. IL-13 is well-documented to promote immunoglobulin production, particularly IgE class switching, in cooperation with IL-4. UniProt function annotation states IL-13 "stimulates B-cell proliferation" (PMID:7903680). The deep research confirms that IL-13 cooperates with IL-4 for IgE biology. Supporting Evidence: PMID:7903680 Interleukin 13 is a B cell stimulating factor PMID:8096327 Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses file:human/IL13/IL13-deep-research-falcon.md IL-13 cooperates with IL-4 for IgE biology through IL-4-dominant class-switch signals while IL-13 predominantly modulates structural cells
GO:0005144 interleukin-13 receptor binding	IBA GO_REF:0000033	ACCEPT	Summary: IL-13 binds its cognate receptors IL-13Ralpha1 (as part of the type II receptor complex) and IL-13Ralpha2 (decoy receptor). This is the defining molecular function of IL-13 as a ligand. Structural studies confirm this binding (PMID:20223216, PMID:11419948). Reason: This is the most specific and accurate molecular function term for IL-13. IL-13 receptor binding is its primary molecular activity. Crystal structures of IL-13 bound to IL-13Ralpha2 (PMID:20223216) and NMR studies of receptor assembly (Walker et al. 2023) confirm this. UniProt records interactions with IL13RA1 (7 experiments) and IL13RA2 (9 experiments). Supporting Evidence: PMID:20223216 Molecular basis for shared cytokine recognition revealed in the structure of an unusually high affinity complex between IL-13 and IL-13Ralpha2 PMID:9013879 Cloning of the human IL-13R alpha1 chain and reconstitution with the IL4R alpha of a functional IL-4/IL-13 receptor complex
GO:0005615 extracellular space	IBA GO_REF:0000033	ACCEPT	Summary: IL-13 is a secreted cytokine that functions in the extracellular space. UniProt annotation indicates it is secreted and has a signal peptide (residues 1-24). Reason: IBA annotation is correct. IL-13 is a secreted cytokine with a signal peptide, confirmed by UniProt subcellular location annotation as "Secreted." It functions extracellularly by binding cell-surface receptors. Supporting Evidence: PMID:8096327 Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses
GO:0006954 inflammatory response	IBA GO_REF:0000033	ACCEPT	Summary: IL-13 plays a complex role in inflammation -- it is a type-2 cytokine that drives allergic inflammation while also having anti-inflammatory effects on certain proinflammatory pathways. UniProt states it "plays important roles in allergic inflammation." Reason: IBA annotation is appropriate. IL-13 is a central mediator of allergic/type-2 inflammation in airways (asthma), skin (atopic dermatitis), and gut. It drives eosinophil recruitment via VCAM-1 induction (PMID:8639787) and promotes mucus hypersecretion and tissue remodeling. The original discovery paper explicitly identifies it as "regulating inflammatory and immune responses" (PMID:8096327). Supporting Evidence: PMID:8096327 Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses PMID:8639787 Interleukin-4 (IL-4) and IL-13 bind to a shared heterodimeric complex on endothelial cells mediating vascular cell adhesion molecule-1 induction
GO:0005125 cytokine activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA from UniProt keyword mapping. IL-13 is indeed a cytokine -- this is confirmed by experimental IDA evidence (PMID:8096327) as well. This IEA is redundant with the IDA annotation but not incorrect. Reason: Correct IEA annotation. IL-13 has experimentally confirmed cytokine activity (IDA, PMID:8096327). The IEA is broader in source (keyword mapping) but correctly captures this core function.
GO:0005126 cytokine receptor binding	IEA GO_REF:0000002	ACCEPT	Summary: IEA from InterPro domain mapping. IL-13 does bind cytokine receptors. However, the more specific term GO:0005144 (interleukin-13 receptor binding) is already annotated. Reason: This is a correct parent term of GO:0005144 (interleukin-13 receptor binding). While more general than the IBA annotation, it is not incorrect as an IEA. The more specific term is captured by IBA evidence.
GO:0005576 extracellular region	IEA GO_REF:0000120	ACCEPT	Summary: Combined automated annotation. IL-13 is a secreted cytokine localized to the extracellular region. Consistent with UniProt "Secreted" annotation and IDA evidence (PMID:20041150). Reason: Correct IEA annotation. IL-13 has a signal peptide and is secreted, confirmed by multiple lines of evidence including IDA and TAS (Reactome).
GO:0005615 extracellular space	IEA GO_REF:0000120	ACCEPT	Summary: Combined automated annotation for extracellular space. Consistent with IBA annotation and the secreted nature of IL-13. Reason: Correct IEA annotation, redundant with IBA annotation for the same term.
GO:0006955 immune response	IEA GO_REF:0000002	ACCEPT	Summary: IEA from InterPro mapping for the IL-4/IL-13 family. IL-13 is a key immune cytokine involved in type-2 immunity. Reason: Correct broad annotation. IL-13 is fundamentally an immune cytokine. The term is general but not incorrect for an IEA.
GO:0042116 macrophage activation	IEA GO_REF:0000117	ACCEPT	Summary: ARBA machine learning annotation. IL-13 drives alternative (M2) macrophage activation, a well-characterized function distinct from classical (M1) activation. Reason: IL-13 is a well-known driver of alternative macrophage activation (M2 polarization). The original cloning paper (PMID:8097324) demonstrated effects on monocyte/macrophage function, and this is also supported by IGI evidence (PMID:30634164). Supporting Evidence: PMID:8097324 Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and B-cell function
GO:0005515 protein binding	IPI PMID:18243101 Molecular and structural basis of cytokine receptor pleiotro...	MODIFY	Summary: IPI evidence for binding IL13RA1 (P78552), from IntAct. The interaction is biologically meaningful -- IL-13 binds IL-13Ralpha1 as part of signaling receptor assembly. Reason: "Protein binding" is uninformative. IL-13 binding to IL-13Ralpha1 is better captured by GO:0005144 (interleukin-13 receptor binding), which is already annotated. The IntAct-derived protein binding annotation does not add informative functional content. Proposed replacements: interleukin-13 receptor binding Supporting Evidence: PMID:18243101 The two type II complexes utilize an unusual top-mounted Ig-like domain on IL-13R alpha1 for a novel mode of cytokine engagement that contributes to a reversal in the IL-4 versus IL-13 ternary complex assembly sequences
GO:0005515 protein binding	IPI PMID:20223216 Molecular basis for shared cytokine recognition revealed in ...	MODIFY	Summary: IPI evidence for binding IL13RA1 (P78552) from the crystal structure study. This is well captured by the more specific GO:0005144 term. Reason: "Protein binding" is uninformative. The crystal structure (PMID:20223216) shows IL-13 bound to IL-13Ralpha2 -- better annotated as GO:0005144 (interleukin-13 receptor binding). Proposed replacements: interleukin-13 receptor binding Supporting Evidence: PMID:20223216 IL-13Ralpha2 uses peripheral receptor residues unused in the IL-13/IL-13Ralpha1 complex to generate a larger and more complementary interface for IL-13.
GO:0005515 protein binding	IPI PMID:23972995 Chitinase 3-like 1 regulates cellular and tissue responses v...	MODIFY	Summary: IPI evidence for binding IL13RA2 (Q14627) from IntAct. The interaction with the decoy receptor IL-13Ralpha2 is a real and important interaction for IL-13 biology. Reason: "Protein binding" is uninformative. IL-13 binding to IL-13Ralpha2 is better captured by GO:0005144 (interleukin-13 receptor binding). Proposed replacements: interleukin-13 receptor binding Supporting Evidence: PMID:23972995 Chi3l1 binds to interleukin-13 receptor α2 (IL-13Rα2) and that Chi3l1, IL-13Rα2, and IL-13 are in a multimeric complex.
GO:0005515 protein binding	IPI PMID:27629921 IL-13Rα2 uses TMEM219 in chitinase 3-like-1-induced signalli...	MODIFY	Summary: IPI evidence for binding IL13RA2 (Q14627) from IntAct. Another confirmation of the IL-13/IL-13Ralpha2 interaction. Reason: "Protein binding" is uninformative. Should be annotated as GO:0005144 (interleukin-13 receptor binding). Proposed replacements: interleukin-13 receptor binding Supporting Evidence: PMID:27629921 Here, we demonstrate that the membrane protein, TMEM219, is a binding partner of IL-13Rα2 using yeast two-hybrid, co-immunoprecipitation, co-localization and bimolecular fluorescence complementation assays.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MODIFY	Summary: IPI from BioPlex 3.0 high-throughput AP-MS study showing interaction with IL13RA1. The BioPlex study (Huttlin et al. 2021) is a proteome-scale interactome study. While the interaction is real, "protein binding" is uninformative. Reason: "Protein binding" is uninformative. The BioPlex interaction with IL13RA1 is better captured by GO:0005144 (interleukin-13 receptor binding). Proposed replacements: interleukin-13 receptor binding Supporting Evidence: PMID:33961781 Thousands of interactions assemble proteins into modules that impart spatial and functional organization to the cellular proteome
GO:0001774 microglial cell activation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara transfer from rat IL-13 (P42203). IL-13 can activate microglia as part of neuroinflammation, but this is not a core function and is a secondary downstream effect. Reason: While IL-13 has been reported to affect microglial activation in neuroinflammatory contexts, this is a peripheral/context-dependent effect, not a core function of IL-13. IL-13 primarily acts on epithelial cells, fibroblasts, B cells, and macrophages. Microglial effects are secondary to its general cytokine signaling.
GO:0002639 positive regulation of immunoglobulin production	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl Compara transfer from rat. Redundant with IBA annotation for the same term. Reason: Correct IEA, consistent with IBA annotation and experimental evidence. IL-13 promotes immunoglobulin production, particularly IgE class switching.
GO:0005144 interleukin-13 receptor binding	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl Compara transfer from rat. Redundant with IBA annotation for the same term. Reason: Correct IEA annotation, consistent with IBA and structural data.
GO:0005737 cytoplasm	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara transfer from mouse IL-13 (P20109). IL-13 is synthesized in the cytoplasm before secretion, but its functional localization is extracellular. Reason: IL-13 is synthesized and transits through the secretory pathway, so cytoplasmic localization is transiently true during biosynthesis but not where the protein functions. UniProt annotates it as "Secreted." This annotation is not wrong per se (the protein is present in cytoplasm during synthesis) but is misleading as IL-13 functions extracellularly.
GO:0009612 response to mechanical stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara transfer from rat. IL-13 expression may be modulated by mechanical stimuli in some contexts, but this is not a well-established core function. Reason: This is likely a context-dependent response observed in rat studies. Mechanical stimuli can influence cytokine expression in various tissues, but this is not a core function of IL-13 itself. The annotation reflects a stimulus-response relationship that is secondary.
GO:0009897 external side of plasma membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara transfer from mouse. IL-13 can bind to its receptors on the cell surface, and in that context may be transiently associated with the external side of the plasma membrane. However, IL-13 is primarily a secreted cytokine. Reason: IL-13 may be transiently associated with cell surface receptors, but its primary localization is extracellular (secreted). The external side of plasma membrane localization likely reflects receptor-bound state rather than a primary localization.
GO:0010155 regulation of proton transport	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl Compara transfer from rat. IL-13 may influence ion transport in epithelial cells as a downstream effect of its signaling, but this is a distant downstream effect. Reason: This is a very downstream pleiotropic effect of IL-13 signaling. IL-13 acts on epithelial cells and can alter ion channel expression/activity, but regulation of proton transport is not a specific or direct function of IL-13. This represents over-annotation of a distant downstream consequence.
GO:0010628 positive regulation of gene expression	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl Compara transfer from rat. IL-13 activates STAT6-dependent transcription and positively regulates expression of many genes. This is extremely broad. Reason: While very broad, IL-13 does positively regulate gene expression through JAK-STAT6 signaling. This is consistent with ISS annotation from ARUK-UCL (GO_REF:0000024). As an IEA, the breadth is acceptable.
GO:0030890 positive regulation of B cell proliferation	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl Compara transfer from rat. IL-13 stimulates B cell proliferation, a well-established function. UniProt states IL-13 "stimulates B-cell proliferation" (PMID:7903680). Reason: Well-supported function. Defrance et al. (1994) demonstrated that IL-13 is a B cell stimulating factor that promotes B cell proliferation (PMID:7903680). This is confirmed by UniProt function annotation. Supporting Evidence: PMID:7903680 Interleukin 13 is a B cell stimulating factor
GO:0032496 response to lipopolysaccharide	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara transfer from rat. IL-13 expression can be modulated by LPS in some immune cell contexts, but this is not a core function of IL-13. Reason: LPS can induce cytokine responses including IL-13 in certain contexts, but "response to lipopolysaccharide" describes a stimulus condition rather than a core function of IL-13. This is a peripheral annotation.
GO:0035094 response to nicotine	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl Compara transfer from rat. Nicotine exposure may modulate IL-13 expression or activity, but this is not a core function. Reason: Response to nicotine is not a core or even secondary function of IL-13. This likely reflects a context in which IL-13 levels change upon nicotine exposure, which is a very indirect stimulus-response relationship. Over-annotated.
GO:0043032 positive regulation of macrophage activation	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl Compara transfer from mouse. IL-13 promotes alternative (M2) macrophage activation, a well-known function. Reason: IL-13 is a key driver of alternative macrophage activation (M2 polarization). This is well-established and is consistent with the IGI annotation from PMID:30634164 and the IEA annotation from ARBA.
GO:0043270 positive regulation of monoatomic ion transport	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl Compara transfer from rat. IL-13 may influence ion transport in epithelial cells as a downstream signaling consequence. Reason: This is a distant downstream effect of IL-13 signaling on epithelial cells. Not a core function of IL-13 itself. Over-annotated.
GO:0045471 response to ethanol	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl Compara transfer from rat. Ethanol may modulate IL-13 expression or responses in some contexts. Reason: Response to ethanol is not a meaningful functional annotation for IL-13. This likely reflects an experimental context in rat where ethanol exposure affected IL-13 levels. Over-annotated.
GO:0048661 positive regulation of smooth muscle cell proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara transfer from rat. IL-13 can promote airway smooth muscle cell proliferation, which contributes to airway remodeling in asthma. Reason: IL-13-driven smooth muscle hyperplasia is relevant to airway remodeling in asthma. The deep research confirms IL-13 promotes "airway hyperresponsiveness" and structural cell remodeling. However, this is a downstream tissue-specific effect rather than a core molecular function.
GO:0050714 positive regulation of protein secretion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara transfer from rat. IL-13 can promote secretion of various proteins (e.g., mucins, chemokines) from target cells. Reason: IL-13 induces secretion of mucins (MUC5AC), chemokines, and other proteins from epithelial cells and macrophages. This is a genuine downstream effect but is very broad. Acceptable as a non-core annotation.
GO:0051281 positive regulation of release of sequestered calcium ion into cytosol	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl Compara transfer from rat. IL-13 signaling may influence calcium release in some cell types as a downstream effect. Reason: Calcium signaling modulation is a very downstream and indirect consequence of IL-13 receptor engagement. Not a core or even secondary function. Over-annotated.
GO:0071260 cellular response to mechanical stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara transfer from rat. Related to GO:0009612 (response to mechanical stimulus). Reason: Same rationale as GO:0009612 -- context-dependent response, not a core function of IL-13.
GO:0071635 negative regulation of transforming growth factor beta production	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara transfer from rat. IL-13 has a complex relationship with TGF-beta: IL-13Ralpha2 signaling can induce TGF-beta1 in some contexts, while IL-13 may negatively regulate TGF-beta production in others. Reason: The relationship between IL-13 and TGF-beta is context-dependent and complex. UniProt notes IL-13 can "downregulate synthesis of many proinflammatory cytokines" by similarity. NAS annotations for TGF-beta1 production regulation (PMID:23972995, PMID:38291404) also exist. This is a secondary/context-dependent effect.
GO:0120162 positive regulation of cold-induced thermogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara transfer from mouse. IL-13 has been reported to promote thermogenesis in adipose tissue via ILC2-derived IL-13 signaling to beige fat. Reason: This is a specialized, tissue-specific function of IL-13 in adipose tissue biology. While supported by mouse studies (also annotated as ISS from PMID:24906148), this is not a core function of IL-13 but rather a recently discovered peripheral role.
GO:2000231 positive regulation of pancreatic stellate cell proliferation	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl Compara transfer from rat. IL-13 may promote fibrosis-related cell proliferation in the pancreas. Reason: This is an extremely tissue-specific and indirect downstream effect. While IL-13 can promote fibrosis in various tissues, "positive regulation of pancreatic stellate cell proliferation" is overly specific for a pleiotropic cytokine. This likely reflects a very specific rat study and represents over-annotation.
GO:0005886 plasma membrane	IPI PMID:18243101 Molecular and structural basis of cytokine receptor pleiotro...	KEEP AS NON CORE	Summary: IPI annotation from ComplexPortal indicating IL-13 is located at the plasma membrane. This likely reflects the IL-13/receptor complex at the cell surface. Reason: IL-13 is primarily a secreted cytokine. Its association with the plasma membrane is transient and reflects receptor-bound state. The primary localization annotations should be extracellular region/extracellular space. Supporting Evidence: PMID:18243101 the type II receptor heterodimer signals with different potencies in response to IL-4 versus IL-13 and suggest that the extracellular cytokine-receptor interactions are modulating intracellular membrane-proximal signaling events.
GO:0006915 apoptotic process	NAS PMID:23972995 Chitinase 3-like 1 regulates cellular and tissue responses v...	KEEP AS NON CORE	Summary: NAS from ComplexPortal. IL-13 signaling through IL-13Ralpha2 has been linked to apoptotic processes in some contexts. He et al. (2013) showed Chi3l1 regulates apoptosis via IL-13Ralpha2-dependent mechanisms, with IL-13 being part of the multimeric complex. Reason: PMID:23972995 demonstrates that Chi3l1 regulates oxidant injury, apoptosis, and pyroptosis via IL-13Ralpha2-dependent mechanisms, with IL-13 as part of the multimeric complex. This is a genuine but indirect and context-dependent role for IL-13 in apoptotic signaling, mediated through the Chi3l1/IL-13Ralpha2 axis rather than through the canonical IL-13 signaling pathway. Supporting Evidence: PMID:23972995 Chi3l1 activates macrophage mitogen-activated protein kinase, protein kinase B/AKT, and Wnt/β-catenin signaling and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-β1 production via IL-13Rα2-dependent mechanisms.
GO:0006915 apoptotic process	NAS PMID:35464460 Recent Advances in IL-13Rα2-Directed Cancer Immunotherapy.	KEEP AS NON CORE	Summary: NAS from ComplexPortal. Knudson et al. (2022) review IL-13Ralpha2-directed cancer immunotherapy and note that IL-13-mediated IL-13Ralpha2 signaling promotes tumor cell survival and other processes via STAT6-independent pathways. Reason: PMID:35464460 describes IL-13-mediated signaling through IL-13Ralpha2 as promoting tumor proliferation, cell survival, invasion, and metastasis. The connection to apoptosis is via the regulation of cell survival pathways through IL-13Ralpha2 signaling. This is a non-core, context-dependent function of IL-13 in tumor biology. Supporting Evidence: PMID:35464460 recent studies demonstrated that IL-13-mediated IL-13Rα2 signaling occurs via STAT6-independent pathways, involving activation of activator protein 1 (AP-1) and extracellular signal-related kinase (ERK), promoting tumor invasion, metastasis, and production of transforming growth factor beta (TGFβ)
GO:0007259 cell surface receptor signaling pathway via JAK-STAT	IDA PMID:18243101 Molecular and structural basis of cytokine receptor pleiotro...	ACCEPT	Summary: IDA from ComplexPortal. IL-13 signals through the type II IL-4 receptor (IL-13Ralpha1/IL-4Ralpha) to activate JAK1/TYK2 kinases and STAT6. This is the canonical IL-13 signaling mechanism. Reason: This is a core function of IL-13. The type II receptor complex activates JAK1 and TYK2, leading to STAT6 phosphorylation and nuclear translocation. This is confirmed by UniProt function annotation (PMID:9013879) and multiple reviews. The deep research report confirms IL-13 "activates JAK1/TYK2 and predominantly STAT6." Supporting Evidence: PMID:9013879 Cloning of the human IL-13R alpha1 chain and reconstitution with the IL4R alpha of a functional IL-4/IL-13 receptor complex
GO:0032905 transforming growth factor beta1 production	NAS PMID:23972995 Chitinase 3-like 1 regulates cellular and tissue responses v...	KEEP AS NON CORE	Summary: NAS from ComplexPortal. He et al. (2013) demonstrated that Chi3l1 regulates TGF-beta1 production via IL-13Ralpha2-dependent mechanisms, with IL-13 being part of the multimeric signaling complex. Reason: PMID:23972995 shows that TGF-beta1 production is regulated by Chi3l1 via IL-13Ralpha2. IL-13 is part of the multimeric complex with Chi3l1 and IL-13Ralpha2. This TGF-beta1 regulation is a downstream consequence of signaling through the non-canonical IL-13Ralpha2 pathway, making it a non-core, context-dependent function. Supporting Evidence: PMID:23972995 Chi3l1 activates macrophage mitogen-activated protein kinase, protein kinase B/AKT, and Wnt/β-catenin signaling and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-β1 production via IL-13Rα2-dependent mechanisms.
GO:0032908 regulation of transforming growth factor beta1 production	NAS PMID:38291404 IL13Rα2 as a crucial receptor for Chi3l1 in osteoclast diffe...	KEEP AS NON CORE	Summary: NAS from ComplexPortal. Xu et al. (2024) demonstrated IL-13Ralpha2 serves as a receptor for Chi3l1 in osteoclast differentiation via MAPK/AKT pathway. The paper focuses on Chi3l1/IL-13Ralpha2 signaling rather than directly on TGF-beta1 regulation by IL-13. Reason: PMID:38291404 demonstrates IL-13Ralpha2 as a receptor for Chi3l1 that promotes MAPK and AKT activation. While the ComplexPortal NAS annotation links this to TGF-beta1 regulation, the paper primarily focuses on osteoclast differentiation. TGF-beta1 regulation via IL-13Ralpha2 is better supported by PMID:23972995. This is a non-core, context-dependent function. Supporting Evidence: PMID:38291404 IL13Rα2 served as a crucial receptor for Chi3l1, enhancing RANKL-induced MAPK and AKT activation to promote osteoclast differentiation.
GO:0035772 interleukin-13-mediated signaling pathway	IDA PMID:18243101 Molecular and structural basis of cytokine receptor pleiotro...	ACCEPT	Summary: IDA from ComplexPortal. IL-13 is the ligand that initiates the IL-13-mediated signaling pathway by binding its receptor complex. Reason: This is the most specific and appropriate biological process term for IL-13. IL-13 initiates its own signaling pathway by binding IL-13Ralpha1 and recruiting IL-4Ralpha to form the signaling-competent ternary complex. Supporting Evidence: PMID:18243101 Here we present the crystal structures of the complete set of type I (IL-4R alpha/gamma(c)/IL-4) and type II (IL-4R alpha/IL-13R alpha1/IL-4, IL-4R alpha/IL-13R alpha1/IL-13) ternary signaling complexes.
GO:0042531 positive regulation of tyrosine phosphorylation of STAT protein	IDA PMID:18243101 Molecular and structural basis of cytokine receptor pleiotro...	ACCEPT	Summary: IDA from ComplexPortal. IL-13 receptor engagement leads to JAK-mediated tyrosine phosphorylation of STAT6 (and to lesser extent STAT3/STAT1). Reason: This is a direct mechanistic consequence of IL-13 receptor signaling. UniProt confirms IL-13 activates JAK1/TYK2 "leading to the activation of STAT6" (PMID:9013879). Reactome pathway entries (R-HSA-6788582) also document STAT phosphorylation. Supporting Evidence: PMID:9013879 Cloning of the human IL-13R alpha1 chain and reconstitution with the IL4R alpha of a functional IL-4/IL-13 receptor complex
GO:0050728 negative regulation of inflammatory response	NAS PMID:12642602 Enhanced interleukin (IL)-13 responses in mice lacking IL-13...	KEEP AS NON CORE	Summary: NAS from ComplexPortal. IL-13 has anti-inflammatory properties, including suppression of proinflammatory cytokine production (IL-1, IL-6, TNF) by monocytes/macrophages. Wood et al. (2003) showed IL-13Ralpha2-deficient mice display decreased tissue macrophage nitric oxide and IL-12 production, consistent with enhanced IL-13 anti-inflammatory signaling. Reason: IL-13 has dual roles in inflammation -- it promotes allergic/type-2 inflammation while suppressing classical proinflammatory (Th1-driven) responses. UniProt states IL-13 "displays the capacity to antagonize Th1-driven proinflammatory immune response and downregulates synthesis of many proinflammatory cytokines including IL1, IL6, IL10, IL12 and TNF" (by similarity). This is a genuine but secondary/modulatory function. Supporting Evidence: PMID:12642602 IL-13Ralpha2-deficient mice display increased bone marrow macrophage progenitor frequency and decreased tissue macrophage nitric oxide and IL-12 production in response to lipopolysaccharide. These results are consistent with a phenotype of enhanced IL-13 responsiveness
GO:0070371 ERK1 and ERK2 cascade	NAS PMID:23972995 Chitinase 3-like 1 regulates cellular and tissue responses v...	KEEP AS NON CORE	Summary: NAS from ComplexPortal. He et al. (2013) demonstrated that IL-13 activates macrophage ERK1/2 signaling via IL-13Ralpha2-dependent mechanisms. This is distinct from the canonical JAK-STAT6 pathway and involves the Chi3l1/IL-13Ralpha2 multimeric complex. Reason: PMID:23972995 demonstrates IL-13 activates MAPK/ERK signaling in macrophages via IL-13Ralpha2. The paper shows "IL-13 also activates macrophage MAPK and AKT via IL-13Ralpha2- and Chi3l1-dependent pathways." This is a genuine but non-canonical signaling activity, secondary to the core JAK-STAT6 pathway. Supporting Evidence: PMID:23972995 Chi3l1 activates macrophage mitogen-activated protein kinase, protein kinase B/AKT, and Wnt/β-catenin signaling and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-β1 production via IL-13Rα2-dependent mechanisms
GO:0070374 positive regulation of ERK1 and ERK2 cascade	NAS PMID:38291404 IL13Rα2 as a crucial receptor for Chi3l1 in osteoclast diffe...	KEEP AS NON CORE	Summary: NAS from ComplexPortal. Xu et al. (2024) demonstrated that Chi3l1 significantly promoted the RANKL-induced MAPK (ERK/P38/JNK) and AKT pathway activation via IL-13Ralpha2. Reason: PMID:38291404 demonstrates IL-13Ralpha2 as a receptor mediating MAPK/ERK activation in the context of osteoclast differentiation. The annotation captures a genuine but context-dependent function of IL-13 receptor signaling. Same considerations as GO:0070371 -- this is a non-canonical pathway. Supporting Evidence: PMID:38291404 Chi3l1 significantly promoted the RANKL-induced MAPK (ERK/P38/JNK) and AKT pathway activation, whereas Chi3l1 silencing inhibited this process
GO:0005125 cytokine activity	IDA PMID:8096327 Interleukin-13 is a new human lymphokine regulating inflamma...	ACCEPT	Summary: IDA from UniProt based on the original discovery/cloning paper by Minty et al. (1993). IL-13 was identified as a new human lymphokine with cytokine activity -- it regulated inflammatory and immune responses. Reason: This is the core molecular function of IL-13. The original paper (PMID:8096327) demonstrated that IL-13 is a cytokine that regulates inflammatory and immune responses and synergizes with IL-2 in regulating interferon-gamma synthesis. This is the primary experimental evidence for cytokine activity. Supporting Evidence: PMID:8096327 Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses
GO:0035772 interleukin-13-mediated signaling pathway	IDA PMID:8096327 Interleukin-13 is a new human lymphokine regulating inflamma...	ACCEPT	Summary: IDA from UniProt. The original discovery paper established IL-13 as the ligand initiating its signaling pathway. Reason: The original cloning and characterization paper is appropriate evidence that IL-13 initiates its own signaling pathway. Supporting Evidence: PMID:8096327 Recombinant IL-13 protein inhibits inflammatory cytokine production induced by lipopolysaccharide in human peripheral blood monocytes. Moreover, it synergizes with IL-2 in regulating interferon-gamma synthesis in large granular lymphocytes.
GO:0035772 interleukin-13-mediated signaling pathway	IDA PMID:12574355 Human activation-induced cytidine deaminase is induced by IL...	ACCEPT	Summary: IDA from ARUK-UCL. Zhou et al. (2003) demonstrated that IL-4 (and by extension IL-13 through shared receptor signaling) induces AID expression via JAK/STAT6 signaling pathway in human B cells. Reason: PMID:12574355 demonstrates IL-4/IL-13 signaling via JAK/STAT6 pathway in B cells, leading to AID induction. The paper states "IL-4-dependent AID induction was inhibited by a dominant-negative STAT6, indicating that IL-4 induced AID expression via the Janus kinase (JAK)/STAT6 signaling pathway." IL-13 shares this signaling through the type II receptor. Supporting Evidence: PMID:12574355 IL-4-dependent AID induction was inhibited by a dominant-negative STAT6, indicating that IL-4 induced AID expression via the Janus kinase (JAK)/STAT6 signaling pathway
GO:0045944 positive regulation of transcription by RNA polymerase II	IGI PMID:12574355 Human activation-induced cytidine deaminase is induced by IL...	KEEP AS NON CORE	Summary: IGI from ARUK-UCL with CD40 (P29965). Zhou et al. showed IL-4/IL-13 signaling induces AID transcription, with CD40 signaling providing enhancement. This represents STAT6-dependent transcriptional activation. Reason: IL-13 signaling via STAT6 activates transcription of many target genes including AID. The term "positive regulation of transcription by RNA polymerase II" is very broad and reflects the downstream transcriptional consequences of IL-13/STAT6 signaling. This is a real but non-core annotation (many signaling molecules regulate transcription). Supporting Evidence: PMID:12574355 IL-4 was able to induce AID expression in human primary B cells and B cell lines, and IL-4-induced AID expression was further enhanced by CD40 signaling
GO:0032733 positive regulation of interleukin-10 production	IGI PMID:30634164 IL-16 regulates macrophage polarization as a target gene of ...	KEEP AS NON CORE	Summary: IGI from ARUK-UCL with IL-4 (P05112). IL-13, together with IL-4, promotes IL-10 production by macrophages as part of the anti-inflammatory M2 polarization program. Reason: IL-13-driven IL-10 production is part of the alternative macrophage activation program and the anti-inflammatory arm of type-2 immunity. This is a genuine but secondary downstream effect of IL-13 signaling. Supporting Evidence: PMID:30634164 THP-1 cells were induced by IL-4 and IL-13 following PMA incubation (M2 polarized macrophages) or induced by IFN-gamma and LPS (M1 classical macrophage activation)
GO:0042116 macrophage activation	IGI PMID:30634164 IL-16 regulates macrophage polarization as a target gene of ...	ACCEPT	Summary: IGI from ARUK-UCL with IL-4 (P05112). IL-13 and IL-4 cooperate in driving alternative macrophage activation (M2 polarization). Reason: Alternative macrophage activation by IL-13 is a well-established core function. The original paper by McKenzie et al. (PMID:8097324) demonstrated IL-13 regulates human monocyte function. The IGI annotation with IL-4 correctly captures the cooperative nature of IL-4/IL-13 in M2 polarization. Supporting Evidence: PMID:8097324 Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and B-cell function
GO:0050728 negative regulation of inflammatory response	IGI PMID:30634164 IL-16 regulates macrophage polarization as a target gene of ...	KEEP AS NON CORE	Summary: IGI from ARUK-UCL with IL-4 (P05112). IL-13 and IL-4 cooperate to suppress proinflammatory responses, consistent with their anti-inflammatory M2 polarization role. Reason: Same rationale as the NAS annotation for this term. IL-13 has anti-inflammatory properties through suppression of Th1 cytokines and M2 macrophage polarization. The IGI evidence with IL-4 strengthens this annotation, but it remains a secondary/modulatory function. Supporting Evidence: PMID:30634164 IL-16 modulates macrophage polarization through regulating IL-10, IL-1a and IL-6 expression. Mir-145 is involved in M2 macrophage polarization by targeting IL-16 and enhancing IL-10 expression.
GO:0010628 positive regulation of gene expression	ISS GO_REF:0000024	ACCEPT	Summary: ISS from ARUK-UCL based on ortholog transfer from rat IL-13 (P42203). IL-13 activates STAT6-dependent gene expression programs. Reason: Correct ISS annotation. IL-13 signaling through STAT6 positively regulates expression of many target genes. This is consistent with IEA annotation for the same term.
GO:0120162 positive regulation of cold-induced thermogenesis	ISS PMID:24906148 Eosinophils and type 2 cytokine signaling in macrophages orc...	KEEP AS NON CORE	Summary: ISS from YuBioLab based on mouse IL-13 (P20109). IL-13 produced by ILC2s promotes beige fat thermogenesis. Reason: This is a specialized metabolic function of IL-13 in adipose tissue biology, not a core immune function. While interesting and supported by mouse studies, cold-induced thermogenesis is a peripheral role of IL-13. Supporting Evidence: PMID:24906148 Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced biogenesis of beige fat
GO:1903660 negative regulation of complement-dependent cytotoxicity	IMP PMID:16034134 IL-4 and IL-13 induce protection of porcine endothelial cell...	KEEP AS NON CORE	Summary: IMP from AgBase. Grehan et al. (2005) demonstrated that porcine endothelial cells incubated with IL-13 became protected from killing by human complement through activation of a PI3K/Akt signaling pathway. Maximal protection required 10 ng/ml IL-13 and developed progressively from 12 to 72 h. Reason: PMID:16034134 provides direct experimental evidence that IL-13 protects endothelial cells from complement-mediated killing via PI3K/Akt pathway activation. This is a genuine cytoprotective function but is context-specific (xenotransplantation model) and secondary to the core immune signaling functions. Supporting Evidence: PMID:16034134 porcine EC incubated with IL-4 or IL-13, but not with IL-10 or IL-11, became protected from killing by complement and apoptosis induced by TNF-alpha plus cycloheximide
GO:2000352 negative regulation of endothelial cell apoptotic process	IMP PMID:16034134 IL-4 and IL-13 induce protection of porcine endothelial cell...	KEEP AS NON CORE	Summary: IMP from AgBase. Grehan et al. (2005) demonstrated that IL-13 protects porcine endothelial cells from apoptosis induced by TNF-alpha plus cycloheximide through activation of the PI3K/Akt signaling pathway, including rapid phosphorylation of Akt. Reason: PMID:16034134 provides direct experimental evidence that IL-13 protects endothelial cells from apoptosis through PI3K/Akt. The paper states IL-4 and IL-13 "can induce protection of porcine EC against killing by apoptosis and human complement through activation of the PI3K/Akt signaling pathway." This is a genuine but context-specific cytoprotective function. Supporting Evidence: PMID:16034134 IL-4 and IL-13 can induce protection of porcine EC against killing by apoptosis and human complement through activation of the PI3K/Akt signaling pathway
GO:0005576 extracellular region	TAS Reactome:R-HSA-449818	ACCEPT	Summary: TAS from Reactome reaction "IL13 binds IL13RA2." IL-13 is in the extracellular region when it binds its decoy receptor. Reason: Correct. IL-13 is extracellular when it engages IL-13Ralpha2.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6786050	ACCEPT	Summary: TAS from Reactome. IL-13 is extracellular in the context of receptor phosphorylation events. Reason: Correct. IL-13 is extracellular during receptor complex signaling.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6786110	ACCEPT	Summary: TAS from Reactome reaction "JAK1 binds IL4R in IL13-bound IL13R type II." Reason: Correct. IL-13 is extracellular in this reaction context.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6786114	ACCEPT	Summary: TAS from Reactome reaction "IL13:IL13RA:TYK2 binds IL4R:JAK2." Reason: Correct. IL-13 is extracellular in this receptor assembly reaction.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6786118	ACCEPT	Summary: TAS from Reactome reaction "IL13 binds IL13RA:TYK2." Reason: Correct. IL-13 is extracellular when binding its receptor.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6788571	ACCEPT	Summary: TAS from Reactome reaction "STAT1,STAT3,STAT6 bind IL13:IL13R type II." Reason: Correct. IL-13 is extracellular in the context of its receptor complex.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6788582	ACCEPT	Summary: TAS from Reactome reaction "STAT1,STAT3,STAT6 phosphorylation." Reason: Correct. IL-13 is extracellular in the receptor signaling context.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6788628	ACCEPT	Summary: TAS from Reactome reaction "p-Y-STATs dissociate." Reason: Correct. IL-13 is extracellular in the signaling complex context.
GO:1901247 negative regulation of lung ciliated cell differentiation	NAS PMID:20539013 Goblet cells are derived from a FOXJ1-expressing progenitor ...	ACCEPT	Summary: NAS from BHF-UCL. IL-13 suppresses ciliated cell differentiation in lung epithelium while promoting goblet cell metaplasia. This is a key mechanism of airway remodeling in asthma. Reason: IL-13-driven mucus metaplasia involves shifting airway epithelial cell differentiation away from ciliated cells toward goblet cells. This is a well-established mechanism in asthma pathogenesis. The deep research confirms IL-13 drives "mucus metaplasia (goblet cell hyperplasia, MUC5AC)." Supporting Evidence: PMID:20539013 Treatment of differentiated HBEC cultures with the cytokine IL-13, an important mediator in asthma, increased the numbers of goblet cells and decreased the numbers of ciliated cells
GO:1901251 positive regulation of lung goblet cell differentiation	NAS PMID:20539013 Goblet cells are derived from a FOXJ1-expressing progenitor ...	ACCEPT	Summary: NAS from BHF-UCL. IL-13 promotes goblet cell differentiation in lung epithelium, the hallmark of mucus metaplasia in asthma. Reason: Goblet cell metaplasia driven by IL-13 is one of its most characteristic and well-studied functions in the airway. This is a core function of IL-13 in the context of airway disease and type-2 immunity. Supporting Evidence: PMID:20539013 IL-13 treatment significantly increased the numbers of EGFP-labeled goblet cells. This study demonstrates that goblet cells formed in response to IL-13 treatment are in part or wholly derived from progenitors that express the ciliated cell marker, FOXJ1.
GO:0005576 extracellular region	IDA PMID:20041150 Missense mutations in the MEFV gene are associated with fibr...	ACCEPT	Summary: IDA from BHF-UCL. The cited reference (PMID:20041150, Feng et al. 2009) is about MEFV gene mutations in fibromyalgia and IL-1beta levels. The paper measures IL-13 plasma levels as one of several cytokines in fibromyalgia patients, but it is primarily about the MEFV gene, not IL-13 localization. Reason: While the cited paper is not primarily about IL-13, the fact that IL-13 was measured in plasma does provide evidence that it is found in the extracellular region. The annotation is technically correct (IL-13 is indeed in the extracellular region), even if the supporting reference is incidental. This is also supported by multiple other annotations (TAS from Reactome, IBA, IEA, and ISS). Supporting Evidence: PMID:20041150 FMS patients and family members without rare variants differed from control subjects with regard to both TH1 (IFNγ) and TH2 (IL-5 and IL-13) cytokine levels (Figure S2).
GO:0005615 extracellular space	ISS PMID:16275384 Allergic dysregulation and hyperimmunoglobulinemia E in Foxp...	ACCEPT	Summary: ISS from UniProt based on mouse IL-13 (P20109). IL-13 is found in the extracellular space as a secreted cytokine. Reason: Correct ISS annotation. IL-13 is a secreted cytokine found in the extracellular space. Consistent with IBA and IEA annotations. Supporting Evidence: PMID:16275384 Foxp3 mutant mice developed an intense multiorgan inflammatory response associated with allergic airway inflammation, a striking hyperimmunoglobulinemia E, eosinophilia, and dysregulated T(H)1 and T(H)2 cytokine production
GO:0006954 inflammatory response	TAS PMID:8096327 Interleukin-13 is a new human lymphokine regulating inflamma...	ACCEPT	Summary: TAS from PINC based on the original IL-13 discovery paper. IL-13 regulates inflammatory and immune responses. Reason: Correct TAS annotation. The original paper by Minty et al. (1993) established IL-13 as a regulator of inflammatory responses. Redundant with IBA annotation for the same term but provides additional evidence support. Supporting Evidence: PMID:8096327 Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses
GO:0043306 positive regulation of mast cell degranulation	IEA GO_REF:0000107	NEW	Summary: IL-13 activates mast cells and promotes their degranulation. UniProt states IL-13 stimulates "activation of eosinophils, basophils, and mast cells" (PMID:8759755). This term is present in the UniProt GO annotations but was missing from the GOA tsv import. Adding for completeness. Reason: IL-13 promotes mast cell activation and degranulation. UniProt explicitly notes this function. This annotation was present in UniProt GO cross-references but not captured in the GOA download. Supporting Evidence: PMID:8759755 Activation of human eosinophils by IL-13

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

📄 View Raw YAML