IL13

id: P35225
gene_symbol: IL13
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Interleukin-13 (IL-13) is a secreted four-alpha-helix bundle cytokine
  of the IL-4/IL-13 family, produced primarily by Th2 cells and type 2 innate lymphoid
  cells (ILC2s), with additional contributions from mast cells and basophils. IL-13
  signals through the type II IL-4 receptor (IL-13Ralpha1/IL-4Ralpha heterodimer)
  to activate JAK1/TYK2 kinases and predominantly STAT6 transcription factor. It drives
  hallmark type-2 immune programs including mucus metaplasia (goblet cell hyperplasia,
  MUC5AC induction), IgE class switching (in cooperation with IL-4), subepithelial
  fibrosis, airway smooth muscle hyperresponsiveness, and epithelial barrier dysregulation.
  IL-13 also binds IL-13Ralpha2, a high-affinity decoy/scavenger receptor that limits
  signaling. IL-13 is central to the pathogenesis of asthma, atopic dermatitis, and
  eosinophilic esophagitis, and is the target of therapeutic antibodies (tralokinumab,
  lebrikizumab) and the dual IL-4/IL-13 blocker dupilumab.
existing_annotations:
- term:
    id: GO:0002639
    label: positive regulation of immunoglobulin production
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:7903680
      supporting_text: Interleukin 13 is a B cell stimulating factor
    - reference_id: PMID:8096327
      supporting_text: Interleukin-13 is a new human lymphokine regulating inflammatory
        and immune responses
    - reference_id: file:human/IL13/IL13-deep-research-falcon.md
      supporting_text: IL-13 cooperates with IL-4 for IgE biology through IL-4-dominant
        class-switch signals while IL-13 predominantly modulates structural cells
- term:
    id: GO:0005144
    label: interleukin-13 receptor binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:20223216
      supporting_text: Molecular basis for shared cytokine recognition revealed in
        the structure of an unusually high affinity complex between IL-13 and IL-13Ralpha2
    - reference_id: PMID:9013879
      supporting_text: Cloning of the human IL-13R alpha1 chain and reconstitution
        with the IL4R alpha of a functional IL-4/IL-13 receptor complex
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:8096327
      supporting_text: Interleukin-13 is a new human lymphokine regulating inflammatory
        and immune responses
- term:
    id: GO:0006954
    label: inflammatory response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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."
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:8096327
      supporting_text: Interleukin-13 is a new human lymphokine regulating inflammatory
        and immune responses
    - reference_id: PMID:8639787
      supporting_text: Interleukin-4 (IL-4) and IL-13 bind to a shared heterodimeric
        complex on endothelial cells mediating vascular cell adhesion molecule-1 induction
- term:
    id: GO:0005125
    label: cytokine activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0005126
    label: cytokine receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    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).
    action: ACCEPT
    reason: Correct IEA annotation. IL-13 has a signal peptide and is secreted, confirmed
      by multiple lines of evidence including IDA and TAS (Reactome).
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Combined automated annotation for extracellular space. Consistent with
      IBA annotation and the secreted nature of IL-13.
    action: ACCEPT
    reason: Correct IEA annotation, redundant with IBA annotation for the same term.
- term:
    id: GO:0006955
    label: immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: IEA from InterPro mapping for the IL-4/IL-13 family. IL-13 is a key immune
      cytokine involved in type-2 immunity.
    action: ACCEPT
    reason: Correct broad annotation. IL-13 is fundamentally an immune cytokine. The
      term is general but not incorrect for an IEA.
- term:
    id: GO:0042116
    label: macrophage activation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: ARBA machine learning annotation. IL-13 drives alternative (M2) macrophage
      activation, a well-characterized function distinct from classical (M1) activation.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:8097324
      supporting_text: Interleukin 13, a T-cell-derived cytokine that regulates human
        monocyte and B-cell function
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18243101
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0005144
      label: interleukin-13 receptor binding
    supported_by:
    - reference_id: PMID:18243101
      supporting_text: 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
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20223216
  review:
    summary: IPI evidence for binding IL13RA1 (P78552) from the crystal structure
      study. This is well captured by the more specific GO:0005144 term.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0005144
      label: interleukin-13 receptor binding
    supported_by:
    - reference_id: PMID:20223216
      supporting_text: 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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23972995
  review:
    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.
    action: MODIFY
    reason: '"Protein binding" is uninformative. IL-13 binding to IL-13Ralpha2 is
      better captured by GO:0005144 (interleukin-13 receptor binding).'
    proposed_replacement_terms:
    - id: GO:0005144
      label: interleukin-13 receptor binding
    supported_by:
    - reference_id: PMID:23972995
      supporting_text: Chi3l1 binds to interleukin-13 receptor α2 (IL-13Rα2) and that
        Chi3l1, IL-13Rα2, and IL-13 are in a multimeric complex.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27629921
  review:
    summary: IPI evidence for binding IL13RA2 (Q14627) from IntAct. Another confirmation
      of the IL-13/IL-13Ralpha2 interaction.
    action: MODIFY
    reason: '"Protein binding" is uninformative. Should be annotated as GO:0005144
      (interleukin-13 receptor binding).'
    proposed_replacement_terms:
    - id: GO:0005144
      label: interleukin-13 receptor binding
    supported_by:
    - reference_id: PMID:27629921
      supporting_text: 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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    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.
    action: MODIFY
    reason: '"Protein binding" is uninformative. The BioPlex interaction with IL13RA1
      is better captured by GO:0005144 (interleukin-13 receptor binding).'
    proposed_replacement_terms:
    - id: GO:0005144
      label: interleukin-13 receptor binding
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Thousands of interactions assemble proteins into modules that
        impart spatial and functional organization to the cellular proteome
- term:
    id: GO:0001774
    label: microglial cell activation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0002639
    label: positive regulation of immunoglobulin production
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl Compara transfer from rat. Redundant with IBA annotation for
      the same term.
    action: ACCEPT
    reason: Correct IEA, consistent with IBA annotation and experimental evidence.
      IL-13 promotes immunoglobulin production, particularly IgE class switching.
- term:
    id: GO:0005144
    label: interleukin-13 receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl Compara transfer from rat. Redundant with IBA annotation for
      the same term.
    action: ACCEPT
    reason: Correct IEA annotation, consistent with IBA and structural data.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl Compara transfer from mouse IL-13 (P20109). IL-13 is synthesized
      in the cytoplasm before secretion, but its functional localization is extracellular.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0009612
    label: response to mechanical stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0009897
    label: external side of plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0010155
    label: regulation of proton transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl Compara transfer from rat. IL-13 activates STAT6-dependent transcription
      and positively regulates expression of many genes. This is extremely broad.
    action: ACCEPT
    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.
- term:
    id: GO:0030890
    label: positive regulation of B cell proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:7903680
      supporting_text: Interleukin 13 is a B cell stimulating factor
- term:
    id: GO:0032496
    label: response to lipopolysaccharide
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0035094
    label: response to nicotine
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl Compara transfer from rat. Nicotine exposure may modulate IL-13
      expression or activity, but this is not a core function.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0043032
    label: positive regulation of macrophage activation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl Compara transfer from mouse. IL-13 promotes alternative (M2)
      macrophage activation, a well-known function.
    action: ACCEPT
    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.
- term:
    id: GO:0043270
    label: positive regulation of monoatomic ion transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl Compara transfer from rat. IL-13 may influence ion transport
      in epithelial cells as a downstream signaling consequence.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is a distant downstream effect of IL-13 signaling on epithelial cells.
      Not a core function of IL-13 itself. Over-annotated.
- term:
    id: GO:0045471
    label: response to ethanol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl Compara transfer from rat. Ethanol may modulate IL-13 expression
      or responses in some contexts.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0048661
    label: positive regulation of smooth muscle cell proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl Compara transfer from rat. IL-13 can promote airway smooth muscle
      cell proliferation, which contributes to airway remodeling in asthma.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0050714
    label: positive regulation of protein secretion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl Compara transfer from rat. IL-13 can promote secretion of various
      proteins (e.g., mucins, chemokines) from target cells.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0051281
    label: positive regulation of release of sequestered calcium ion into cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl Compara transfer from rat. IL-13 signaling may influence calcium
      release in some cell types as a downstream effect.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0071260
    label: cellular response to mechanical stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl Compara transfer from rat. Related to GO:0009612 (response to
      mechanical stimulus).
    action: KEEP_AS_NON_CORE
    reason: Same rationale as GO:0009612 -- context-dependent response, not a core
      function of IL-13.
- term:
    id: GO:0071635
    label: negative regulation of transforming growth factor beta production
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.'
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0120162
    label: positive regulation of cold-induced thermogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:2000231
    label: positive regulation of pancreatic stellate cell proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ensembl Compara transfer from rat. IL-13 may promote fibrosis-related
      cell proliferation in the pancreas.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IPI
  original_reference_id: PMID:18243101
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:18243101
      supporting_text: 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.
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: NAS
  original_reference_id: PMID:23972995
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:23972995
      supporting_text: 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.
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: NAS
  original_reference_id: PMID:35464460
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:35464460
      supporting_text: 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)
- term:
    id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  evidence_type: IDA
  original_reference_id: PMID:18243101
  review:
    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.
    action: ACCEPT
    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."
    supported_by:
    - reference_id: PMID:9013879
      supporting_text: Cloning of the human IL-13R alpha1 chain and reconstitution
        with the IL4R alpha of a functional IL-4/IL-13 receptor complex
- term:
    id: GO:0032905
    label: transforming growth factor beta1 production
  evidence_type: NAS
  original_reference_id: PMID:23972995
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:23972995
      supporting_text: 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.
- term:
    id: GO:0032908
    label: regulation of transforming growth factor beta1 production
  evidence_type: NAS
  original_reference_id: PMID:38291404
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:38291404
      supporting_text: IL13Rα2 served as a crucial receptor for Chi3l1, enhancing
        RANKL-induced MAPK and AKT activation to promote osteoclast differentiation.
- term:
    id: GO:0035772
    label: interleukin-13-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:18243101
  review:
    summary: IDA from ComplexPortal. IL-13 is the ligand that initiates the IL-13-mediated
      signaling pathway by binding its receptor complex.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:18243101
      supporting_text: Here we present the crystal structures of the complete set
        of type I (IL-4R alpha/gamma(c)/IL-4) and type II (IL-4R alpha/IL-13R alpha1/IL-4,
        IL-4R alpha/IL-13R alpha1/IL-13) ternary signaling complexes.
- term:
    id: GO:0042531
    label: positive regulation of tyrosine phosphorylation of STAT protein
  evidence_type: IDA
  original_reference_id: PMID:18243101
  review:
    summary: IDA from ComplexPortal. IL-13 receptor engagement leads to JAK-mediated
      tyrosine phosphorylation of STAT6 (and to lesser extent STAT3/STAT1).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:9013879
      supporting_text: Cloning of the human IL-13R alpha1 chain and reconstitution
        with the IL4R alpha of a functional IL-4/IL-13 receptor complex
- term:
    id: GO:0050728
    label: negative regulation of inflammatory response
  evidence_type: NAS
  original_reference_id: PMID:12642602
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:12642602
      supporting_text: 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
- term:
    id: GO:0070371
    label: ERK1 and ERK2 cascade
  evidence_type: NAS
  original_reference_id: PMID:23972995
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:23972995
      supporting_text: 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
- term:
    id: GO:0070374
    label: positive regulation of ERK1 and ERK2 cascade
  evidence_type: NAS
  original_reference_id: PMID:38291404
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:38291404
      supporting_text: Chi3l1 significantly promoted the RANKL-induced MAPK (ERK/P38/JNK)
        and AKT pathway activation, whereas Chi3l1 silencing inhibited this process
- term:
    id: GO:0005125
    label: cytokine activity
  evidence_type: IDA
  original_reference_id: PMID:8096327
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:8096327
      supporting_text: Interleukin-13 is a new human lymphokine regulating inflammatory
        and immune responses
- term:
    id: GO:0035772
    label: interleukin-13-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:8096327
  review:
    summary: IDA from UniProt. The original discovery paper established IL-13 as the
      ligand initiating its signaling pathway.
    action: ACCEPT
    reason: The original cloning and characterization paper is appropriate evidence
      that IL-13 initiates its own signaling pathway.
    supported_by:
    - reference_id: PMID:8096327
      supporting_text: 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.
- term:
    id: GO:0035772
    label: interleukin-13-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:12574355
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:12574355
      supporting_text: IL-4-dependent AID induction was inhibited by a dominant-negative
        STAT6, indicating that IL-4 induced AID expression via the Janus kinase (JAK)/STAT6
        signaling pathway
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IGI
  original_reference_id: PMID:12574355
  review:
    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.
    action: KEEP_AS_NON_CORE
    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).
    supported_by:
    - reference_id: PMID:12574355
      supporting_text: IL-4 was able to induce AID expression in human primary B cells
        and B cell lines, and IL-4-induced AID expression was further enhanced by
        CD40 signaling
- term:
    id: GO:0032733
    label: positive regulation of interleukin-10 production
  evidence_type: IGI
  original_reference_id: PMID:30634164
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:30634164
      supporting_text: THP-1 cells were induced by IL-4 and IL-13 following PMA incubation
        (M2 polarized macrophages) or induced by IFN-gamma and LPS (M1 classical macrophage
        activation)
- term:
    id: GO:0042116
    label: macrophage activation
  evidence_type: IGI
  original_reference_id: PMID:30634164
  review:
    summary: IGI from ARUK-UCL with IL-4 (P05112). IL-13 and IL-4 cooperate in driving
      alternative macrophage activation (M2 polarization).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:8097324
      supporting_text: Interleukin 13, a T-cell-derived cytokine that regulates human
        monocyte and B-cell function
- term:
    id: GO:0050728
    label: negative regulation of inflammatory response
  evidence_type: IGI
  original_reference_id: PMID:30634164
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:30634164
      supporting_text: 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.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS from ARUK-UCL based on ortholog transfer from rat IL-13 (P42203).
      IL-13 activates STAT6-dependent gene expression programs.
    action: ACCEPT
    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.
- term:
    id: GO:0120162
    label: positive regulation of cold-induced thermogenesis
  evidence_type: ISS
  original_reference_id: PMID:24906148
  review:
    summary: ISS from YuBioLab based on mouse IL-13 (P20109). IL-13 produced by ILC2s
      promotes beige fat thermogenesis.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:24906148
      supporting_text: Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced
        biogenesis of beige fat
- term:
    id: GO:1903660
    label: negative regulation of complement-dependent cytotoxicity
  evidence_type: IMP
  original_reference_id: PMID:16034134
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:16034134
      supporting_text: porcine EC incubated with IL-4 or IL-13, but not with IL-10
        or IL-11, became protected from killing by complement and apoptosis induced
        by TNF-alpha plus cycloheximide
- term:
    id: GO:2000352
    label: negative regulation of endothelial cell apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:16034134
  review:
    summary: 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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:16034134
      supporting_text: IL-4 and IL-13 can induce protection of porcine EC against
        killing by apoptosis and human complement through activation of the PI3K/Akt
        signaling pathway
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-449818
  review:
    summary: TAS from Reactome reaction "IL13 binds IL13RA2." IL-13 is in the extracellular
      region when it binds its decoy receptor.
    action: ACCEPT
    reason: Correct. IL-13 is extracellular when it engages IL-13Ralpha2.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786050
  review:
    summary: TAS from Reactome. IL-13 is extracellular in the context of receptor
      phosphorylation events.
    action: ACCEPT
    reason: Correct. IL-13 is extracellular during receptor complex signaling.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786110
  review:
    summary: TAS from Reactome reaction "JAK1 binds IL4R in IL13-bound IL13R type
      II."
    action: ACCEPT
    reason: Correct. IL-13 is extracellular in this reaction context.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786114
  review:
    summary: TAS from Reactome reaction "IL13:IL13RA:TYK2 binds IL4R:JAK2."
    action: ACCEPT
    reason: Correct. IL-13 is extracellular in this receptor assembly reaction.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786118
  review:
    summary: TAS from Reactome reaction "IL13 binds IL13RA:TYK2."
    action: ACCEPT
    reason: Correct. IL-13 is extracellular when binding its receptor.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788571
  review:
    summary: TAS from Reactome reaction "STAT1,STAT3,STAT6 bind IL13:IL13R type II."
    action: ACCEPT
    reason: Correct. IL-13 is extracellular in the context of its receptor complex.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788582
  review:
    summary: TAS from Reactome reaction "STAT1,STAT3,STAT6 phosphorylation."
    action: ACCEPT
    reason: Correct. IL-13 is extracellular in the receptor signaling context.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788628
  review:
    summary: TAS from Reactome reaction "p-Y-STATs dissociate."
    action: ACCEPT
    reason: Correct. IL-13 is extracellular in the signaling complex context.
- term:
    id: GO:1901247
    label: negative regulation of lung ciliated cell differentiation
  evidence_type: NAS
  original_reference_id: PMID:20539013
  review:
    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.
    action: ACCEPT
    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)."
    supported_by:
    - reference_id: PMID:20539013
      supporting_text: 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
- term:
    id: GO:1901251
    label: positive regulation of lung goblet cell differentiation
  evidence_type: NAS
  original_reference_id: PMID:20539013
  review:
    summary: NAS from BHF-UCL. IL-13 promotes goblet cell differentiation in lung
      epithelium, the hallmark of mucus metaplasia in asthma.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:20539013
      supporting_text: 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.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:20041150
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:20041150
      supporting_text: 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).
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: ISS
  original_reference_id: PMID:16275384
  review:
    summary: ISS from UniProt based on mouse IL-13 (P20109). IL-13 is found in the
      extracellular space as a secreted cytokine.
    action: ACCEPT
    reason: Correct ISS annotation. IL-13 is a secreted cytokine found in the extracellular
      space. Consistent with IBA and IEA annotations.
    supported_by:
    - reference_id: PMID:16275384
      supporting_text: 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
- term:
    id: GO:0006954
    label: inflammatory response
  evidence_type: TAS
  original_reference_id: PMID:8096327
  review:
    summary: TAS from PINC based on the original IL-13 discovery paper. IL-13 regulates
      inflammatory and immune responses.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:8096327
      supporting_text: Interleukin-13 is a new human lymphokine regulating inflammatory
        and immune responses
- term:
    id: GO:0043306
    label: positive regulation of mast cell degranulation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: NEW
    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.
    supported_by:
    - reference_id: PMID:8759755
      supporting_text: Activation of human eosinophils by IL-13
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:8096327
  title: Interleukin-13 is a new human lymphokine regulating inflammatory and immune
    responses.
  findings:
  - statement: Original discovery and cloning of IL-13 as a cytokine produced by activated
      T cells. Demonstrated IL-13 regulates inflammatory and immune responses and
      synergizes with IL-2 in regulating IFN-gamma synthesis.
    supporting_text: 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.
- id: PMID:8097324
  title: Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and
    B-cell function.
  findings:
  - statement: Independent cloning and characterization of IL-13. Showed IL-13 regulates
      monocyte and B cell function, including effects on macrophage activation.
    supporting_text: We show that the human and mouse proteins cause extensive morphological
      changes to human monocytes with an associated up-regulation of major histocompatibility
      complex class II antigens and the low-affinity receptor for immunoglobulin E
      (Fc epsilon RII or CD23).
- id: PMID:7903680
  title: Interleukin 13 is a B cell stimulating factor.
  findings:
  - statement: Demonstrated IL-13 stimulates B cell proliferation and activation,
      and promotes immunoglobulin production.
    supporting_text: it stimulates B cell proliferation in combination with anti-Ig
      and anti-CD40 antibodies; and (c) it induces IgE synthesis
- id: PMID:8759755
  title: "Activation of human eosinophils by IL-13. Induction of CD69 surface antigen, its relationship to messenger RNA expression, and promotion of cellular viability."
  findings:
  - statement: Demonstrated IL-13 activates eosinophils, induces CD69 expression,
      and promotes eosinophil viability.
    supporting_text: our results demonstrate that IL-13 specifically activates human
      eosinophils, as determined by the expression of CD69 cell surface protein and
      mRNA expression. Furthermore, IL-13 significantly prolongs eosinophil survival
      in vitro.
- id: PMID:9013879
  title: Cloning of the human IL-13R alpha1 chain and reconstitution with the IL4R
    alpha of a functional IL-4/IL-13 receptor complex.
  findings:
  - statement: Identified IL-13Ralpha1 and showed it reconstitutes a functional IL-4/IL-13
      receptor with IL-4Ralpha, activating JAK1/TYK2 and STAT6.
    supporting_text: IL-13 and IL-4 were able to activate Stat6 in cells expressing
      both IL-4R alpha and IL-13R alpha1, while no activation was observed in cells
      expressing either one or the other alone.
- id: PMID:8639787
  title: "Interleukin-4 (IL-4) and IL-13 bind to a shared heterodimeric complex on endothelial cells mediating vascular cell adhesion molecule-1 induction in the absence of the common gamma chain."
  findings:
  - statement: Showed IL-4 and IL-13 share a receptor complex on endothelial cells
      and both induce VCAM-1, important for eosinophil recruitment.
    supporting_text: Interleukin-4 (IL-4) and IL-13 exert similar, nonadditive effects
      on endothelial cells, inducing vascular cell adhesion molecule-1 (VCAM-1) expression
      and subsequent transmigration of eosinophils.
- id: PMID:21622864
  title: IL-13 antibodies influence IL-13 clearance in humans by modulating scavenger
    activity of IL-13Rα2.
  findings:
  - statement: Demonstrated IL-13Ralpha2 acts as a high-affinity decoy/scavenger receptor
      that mediates internalization and depletion of extracellular IL-13.
    supporting_text: Cells with high IL-13Ralpha2 expression rapidly and efficiently
      depleted extracellular IL-13, and this activity persisted in the presence of
      IMA-638 but not IMA-026. The potency and efficiency of this clearance pathway
      suggest that cell surface IL-13Ralpha2 acts as a scavenger for IL-13.
- id: PMID:12574355
  title: 'Human activation-induced cytidine deaminase is induced by IL-4 and negatively
    regulated by CD45: implication of CD45 as a Janus kinase phosphatase in antibody
    diversification.'
  findings:
  - statement: Showed IL-4 induces AID expression in B cells via JAK/STAT6 signaling
      pathway, with CD40 signaling enhancing the effect. IL-13 shares this signaling
      mechanism.
    supporting_text: IL-4 was able to induce AID expression in human primary B cells
      and B cell lines, and IL-4-induced AID expression was further enhanced by CD40
      signaling. IL-4-dependent AID induction was inhibited by a dominant-negative
      STAT6, indicating that IL-4 induced AID expression via the Janus kinase (JAK)/STAT6
      signaling pathway.
- id: PMID:12642602
  title: Enhanced interleukin (IL)-13 responses in mice lacking IL-13 receptor alpha
    2.
  findings: []
- id: PMID:16034134
  title: IL-4 and IL-13 induce protection of porcine endothelial cells from killing
    by human complement and from apoptosis through activation of a phosphatidylinositide
    3-kinase/Akt pathway.
  findings: []
- id: PMID:16275384
  title: Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice.
  findings: []
- id: PMID:18243101
  title: Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13
    system.
  findings:
  - statement: Characterization of IL-13 receptor complex including IL-13Ralpha1 interaction
      and JAK-STAT signaling pathway activation.
    supporting_text: Here we present the crystal structures of the complete set of
      type I (IL-4R alpha/gamma(c)/IL-4) and type II (IL-4R alpha/IL-13R alpha1/IL-4,
      IL-4R alpha/IL-13R alpha1/IL-13) ternary signaling complexes.
- id: PMID:20041150
  title: Missense mutations in the MEFV gene are associated with fibromyalgia syndrome
    and correlate with elevated IL-1beta plasma levels.
  findings:
  - statement: Measured IL-13 and other cytokine plasma levels in fibromyalgia patients.
      IL-13 was detected in plasma, confirming its extracellular localization.
    supporting_text: 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
- id: PMID:20223216
  title: Molecular basis for shared cytokine recognition revealed in the structure
    of an unusually high affinity complex between IL-13 and IL-13Ralpha2.
  findings:
  - statement: Solved crystal structure of IL-13 bound to IL-13Ralpha2 at 3.05 angstroms,
      revealing the molecular basis for the high-affinity interaction with the decoy
      receptor.
    supporting_text: 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. This results in a four orders of magnitude increase in affinity,
      to the femtomolar level, compared to IL-13Ralpha1.
- id: PMID:20539013
  title: Goblet cells are derived from a FOXJ1-expressing progenitor in a human airway
    epithelium.
  findings:
  - statement: Demonstrated IL-13 suppresses ciliated cell differentiation while promoting
      goblet cell metaplasia in lung epithelium.
    supporting_text: 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.
- id: PMID:23972995
  title: Chitinase 3-like 1 regulates cellular and tissue responses via IL-13 receptor
    α2.
  findings: []
- id: PMID:24906148
  title: Eosinophils and type 2 cytokine signaling in macrophages orchestrate development
    of functional beige fat.
  findings:
  - statement: Mouse study showing IL-13 from ILC2s promotes beige fat thermogenesis.
    supporting_text: Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced
      biogenesis of beige fat.
- id: PMID:27629921
  title: IL-13Rα2 uses TMEM219 in chitinase 3-like-1-induced signalling and effector
    responses.
  findings: []
- id: PMID:30634164
  title: IL-16 regulates macrophage polarization as a target gene of mir-145-3p.
  findings:
  - statement: Demonstrated IL-4 and IL-13 cooperate in macrophage activation, IL-10
      production, and negative regulation of inflammatory response.
    supporting_text: THP-1 cells were induced by IL-4 and IL-13 following PMA incubation
      (M2 polarized macrophages) or induced by IFN-gamma and LPS (M1 classical macrophage
      activation).
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings:
  - statement: BioPlex 3.0 high-throughput interactome study identifying IL-13 interaction
      with IL-13Ralpha1 among proteome-scale interaction networks.
    supporting_text: Thousands of interactions assemble proteins into modules that
      impart spatial and functional organization to the cellular proteome.
- id: PMID:35464460
  title: Recent Advances in IL-13Rα2-Directed Cancer Immunotherapy.
  findings: []
- id: PMID:38291404
  title: IL13Rα2 as a crucial receptor for Chi3l1 in osteoclast differentiation and
    bone resorption through the MAPK/AKT pathway.
  findings: []
- id: PMID:11419948
  title: Solution structure of human IL-13 and implication for receptor binding.
  findings:
  - statement: Solved NMR structure of IL-13 (residues 35-146), confirming the four-helix
      bundle architecture and identifying receptor binding interfaces.
    supporting_text: The high-resolution solution structure of human IL-13 has been
      determined by multidimensional NMR. The resulting structure is consistent with
      previous short-chain left-handed four-helix bundles, where a significant similarity
      in the folding topology between IL-13 and IL-4 was observed.
- id: Reactome:R-HSA-449818
  title: IL13 binds IL13RA2
  findings: []
- id: Reactome:R-HSA-6786050
  title: IL4R, IL13RA, JAK2 and TYK2 are tyrosine phosphorylated
  findings: []
- id: Reactome:R-HSA-6786110
  title: JAK1 binds IL4R in IL13-bound IL13R type II
  findings: []
- id: Reactome:R-HSA-6786114
  title: IL13:IL13RA:TYK2 binds IL4R:JAK2
  findings: []
- id: Reactome:R-HSA-6786118
  title: IL13 binds IL13RA:TYK2
  findings: []
- id: Reactome:R-HSA-6788571
  title: STAT1,STAT3,STAT6 bind IL13:IL13R type II
  findings: []
- id: Reactome:R-HSA-6788582
  title: STAT1,STAT3,STAT6 phosphorylation
  findings: []
- id: Reactome:R-HSA-6788628
  title: p-Y-STATs dissociate
  findings: []
core_functions:
- molecular_function:
    id: GO:0005144
    label: interleukin-13 receptor binding
  description: IL-13 binds the type II IL-4 receptor complex (IL-13Ralpha1/IL-4Ralpha)
    with sequential assembly -- first binding IL-13Ralpha1, then recruiting IL-4Ralpha.
    Also binds the high-affinity decoy receptor IL-13Ralpha2, which mediates ligand
    clearance. This is the primary molecular function of IL-13 as a signaling ligand.
  directly_involved_in:
  - id: GO:0035772
    label: interleukin-13-mediated signaling pathway
  - id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  - id: GO:0006954
    label: inflammatory response
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: PMID:20223216
    supporting_text: Molecular basis for shared cytokine recognition revealed in the
      structure of an unusually high affinity complex between IL-13 and IL-13Ralpha2
  - reference_id: PMID:9013879
    supporting_text: Cloning of the human IL-13R alpha1 chain and reconstitution with
      the IL4R alpha of a functional IL-4/IL-13 receptor complex
- molecular_function:
    id: GO:0005125
    label: cytokine activity
  description: IL-13 functions as a secreted type-2 cytokine of the four-alpha-helix
    bundle family. It acts on non-hematopoietic structural cells (epithelial cells,
    fibroblasts, smooth muscle) and immune cells (B cells, macrophages, eosinophils)
    to drive type-2 immune programs including IgE class switching, mucus metaplasia,
    and alternative macrophage activation.
  directly_involved_in:
  - id: GO:0002639
    label: positive regulation of immunoglobulin production
  - id: GO:0042116
    label: macrophage activation
  - id: GO:1901251
    label: positive regulation of lung goblet cell differentiation
  - id: GO:1901247
    label: negative regulation of lung ciliated cell differentiation
  - id: GO:0030890
    label: positive regulation of B cell proliferation
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: PMID:8096327
    supporting_text: Interleukin-13 is a new human lymphokine regulating inflammatory
      and immune responses
  - reference_id: PMID:7903680
    supporting_text: Interleukin 13 is a B cell stimulating factor