id: MODULE:il10_signaling title: Interleukin-10 signaling — IL-10 binding to IL10RA and recruitment of IL10RB, JAK1/TYK2 activation, STAT3 docking on phospho-IL10RA and STAT3-driven anti-inflammatory transcription; IL10/IL10RA/IL10RB/JAK1/TYK2/STAT3/STAT1 description: >- Interleukin-10 (IL-10), a domain-swapped homodimeric class II cytokine, binds its high-affinity receptor chain IL10RA (IL-10R1); the IL-10:IL10RA complex then recruits the shared low-affinity chain IL10RB (IL-10R2), which cannot bind IL-10 alone. Assembly of the ternary complex activates JAK1, bound to IL10RA, and TYK2, bound to IL10RB. The kinases phosphorylate two tyrosines in the IL10RA cytoplasmic domain that are the docking sites for STAT3; JAK-phosphorylated STAT3 dimerizes, enters the nucleus and drives the transcriptional programme that suppresses pro-inflammatory cytokine production in monocytes and macrophages. STAT1 (and STAT5 in some cells) is also activated but is not recruited through the STAT3 docking sites. Among the STAT3-induced genes is SOCS3, which does not inhibit the IL-10 receptor itself. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0000515 title: interleukin-10 signaling pathway statement: >- RGD Pathway Ontology diagram from which this module is derived: Il10 binding to Il10ra and Il10rb, Jak1 on Il10ra and Tyk2 on Il10rb phosphorylating Il10ra at two tyrosines, Stat3 recruited to the phosphotyrosine, Stat1 associated with Il10ra, and anti-inflammatory and Th1/Th2 outputs. - source_id: GO:0140105 title: interleukin-10-mediated signaling pathway statement: >- The GO process mapped to PW:0000515 and the concept of this module's root node; it is the process term of the human IL-10 GO-CAM and of the experimental GOA rows on IL10, IL10RA, IL10RB, JAK1, TYK2 and STAT3. - source_id: PMID:31611251 title: Biology and therapeutic potential of interleukin-10. statement: Review used for the overall decomposition into receptor assembly, JAK1/TYK2 and STAT3 steps. supporting_text: >- Binding of IL-10 to its receptor activates a major JAK1-TYK2-STAT3 signaling cascade, which culminates with the induction of the STAT3-mediated anti-inflammatory response. - source_id: PMID:12754507 title: IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. statement: >- Boundary evidence for the SOCS3 decision: SOCS3 is induced by IL-10 but does not block IL-10 receptor signalling, so it is an output of this module, not a feedback part. supporting_text: SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10. - source_id: gomodel:626b20c100000681 title: IL10-mediated signaling pathway (Human) statement: >- Production human GO-CAM realizing this module: IL10 cytokine activity upstream of IL10RA interleukin-10 receptor activity, which is upstream of IL10RB coreceptor activity and JAK1 kinase activity; IL10RB is upstream of TYK2 and JAK1 is upstream of STAT3. Its six activities are pinned to the annotons below. notes: >- Derivation. This module is derived from RGD PW:0000515 (interleukin-10 signaling pathway; 7 RGD-curated human genes: IL10, IL10RA, IL10RB, JAK1, STAT1, STAT3, TYK2). All seven are modelled. The RGD text also describes upstream control of IL10 production (STAT3 downstream of IL-6 and IL-12, TLR2 and pathogen induction) and the many downstream immune effects; IL-10 production is a separate process (GO:0032613) outside this module, and the effects are outputs of the STAT3 transcription step. Relationship to il22_signaling and il6_signaling. IL10RB is the shared second chain of the IL-10, IL-22, IL-26 and type III interferon receptors. modules/il22_signaling.yaml models IL22RA1:IL10RB with JAK1 and TYK2; its receptor-assembly and JAK steps are IL-22-specific (they phosphorylate IL22RA1, not IL10RA), so no step of it is genuinely shared and none is module_ref'd. This module follows its conventions for the shared roles: JAK1 and TYK2 carry non-membrane spanning protein tyrosine kinase activity (GO:0004715) at cytosol/plasma membrane, and STAT3 carries DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981). The one deliberate difference is IL10RB: il22_signaling gives it cytokine receptor activity (GO:0004896, from the PAINT node), whereas here it carries coreceptor activity (GO:0015026), the term of the IDA GOA row (PMID:16982608) and of the IL-10 GO-CAM, matching IL10RB's role as the low-affinity chain that only binds IL-10 after IL10RA has. modules/il6_signaling.yaml is IL-6/gp130-specific and exposes no shared step; it is referenced only for the SOCS3 contrast below. The generic STAT dimerization and nuclear import step and the STAT-dependent transcription step are included by module_ref to jak_stat_signaling#stat_dimerization_import and jak_stat_signaling#stat_transcription. SOCS3 (substrate and target-gene rule). RGD's text says IL-10-induced Socs3 inhibits JAK kinases and may terminate IL-10 effects. SOCS3 is indeed a STAT3 target induced by IL-10, but SOCS3 docks on gp130 and inhibits IL-6 signalling, and in SOCS3-deficient macrophages IL-10 signalling is unchanged (PMID:12754507; PMID:31611251). Being an induced gene is not participation in IL-10 signalling, and SOCS3 does no work at the IL-10 receptor, so SOCS3 is recorded as an output of the transcription step in prose and is not a part. SOCS3 is not on RGD's human gene list for this pathway either. STAT1 and STAT5. IL-10 activates STAT1 in T cells and monocytes and STAT5 in some cells, but the IL10RA phosphotyrosines recruit STAT3 and not STAT1 or STAT5 (PMID:8910398), and STAT3 with JAK1 is required for the anti-inflammatory action (PMID:10347215). STAT1 (on RGD's list) is therefore an optional, accessory part; STAT5 is not modelled. Residue numbering. The two STAT3 docking tyrosines were mapped in the murine receptor (Tyr427 and Tyr477, in the YQKQ and YLKQ motifs). Human residue numbers are not asserted here because they were not verified against the human IL10RA sequence. Functions and their support. IL10 GO:0005125 cytokine activity (IDA; IL10 gene review core function), IL10RA GO:0004920 interleukin-10 receptor activity (IDA), IL10RB GO:0015026 coreceptor activity (IDA), JAK1 and TYK2 GO:0004715 (IDA; gene review core functions), STAT3 and STAT1 GO:0000981 (IDA; gene review core functions). No curator-authored function without an experimental GOA row is used. IL10RA and IL10RB have no local gene review or UniProt file; their accessions were taken from UniProt REST. Participants are GENE_PRODUCT accessions; no PANTHER family or PTN ids are asserted. GO-CAM. gomodel:626b20c100000681 (IL10-mediated signaling pathway, Human) contains six of the seven members and its activities are pinned to the matching annotons. Two differences are recorded, not corrected: the model types STAT3 with the parent GO:0003700 where this module uses the RNA polymerase II-specific child GO:0000981, and the model has no causal edge from TYK2 to STAT3 (only JAK1 is upstream of STAT3), whereas the literature has both kinases phosphorylating the receptor. STAT1 is not in the model. module: id: il10_signaling label: Interleukin-10 signaling pathway module_type: SIGNALING_PATHWAY concepts: - preferred_term: interleukin-10-mediated signaling pathway term: id: GO:0140105 label: interleukin-10-mediated signaling pathway description: >- From IL-10 binding to IL10RA and recruitment of IL10RB, through JAK1/TYK2 activation and STAT3 docking on phospho-IL10RA, to STAT3-dependent anti-inflammatory transcription. context: taxa: - preferred_term: mammals term: id: NCBITaxon:40674 label: Mammalia cellular_components: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: nucleus term: id: GO:0005634 label: nucleus parts: - order: 1 role: receptor complex assembly node: id: il10_receptor_assembly label: IL-10 binds IL10RA and recruits IL10RB module_type: REGULATORY_STEP description: >- The IL-10 dimer binds two IL10RA chains with high affinity; IL10RA binding changes the conformation of IL-10 helix A, creating the site that the low-affinity IL10RB chain then engages, so the active complex is assembled in sequence (IL-10:IL10RA first, then IL10RB) as a 2:2:2-type ternary complex at the plasma membrane. concepts: - preferred_term: interleukin-10 receptor complex term: id: GO:1905571 label: interleukin-10 receptor complex annotons: - id: il10_cytokine label: Interleukin-10 cytokine participant: selector_type: GENE_PRODUCT gene_product: preferred_term: IL10 term: id: UniProtKB:P22301 label: Interleukin-10 function: preferred_term: cytokine activity term: id: GO:0005125 label: cytokine activity processes: - preferred_term: interleukin-10-mediated signaling pathway term: id: GO:0140105 label: interleukin-10-mediated signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Secreted homodimeric ligand; binds IL10RA first and, once bound, presents the site recognised by IL10RB. evidence: - source_id: PMID:11485736 statement: The IL-10:IL-10R1 intermediate must recruit IL-10R2 before signalling. supporting_text: >- This intermediate complex must subsequently recruit the low-affinity IL-10R2 chain before cell signaling can occur. - source_id: file:genes/human/IL10/IL10-ai-review.yaml statement: The IL10 gene review's core functions are cytokine activity (GO:0005125) and IL-10 receptor binding. gocam_associations: - model: gomodel:626b20c100000681 activity: gomodel:626b20c100000681/626b20c100000682 title: IL10 cytokine activity (GO:0005125), IL10-mediated signaling pathway (Human) - id: il10ra_receptor label: IL10RA ligand-binding receptor chain participant: selector_type: GENE_PRODUCT gene_product: preferred_term: IL10RA term: id: UniProtKB:Q13651 label: Interleukin-10 receptor subunit alpha function: preferred_term: interleukin-10 receptor activity term: id: GO:0004920 label: interleukin-10 receptor activity processes: - preferred_term: interleukin-10-mediated signaling pathway term: id: GO:0140105 label: interleukin-10-mediated signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- IL-10-specific high-affinity chain, largely restricted to haematopoietic cells; binds JAK1 and, after phosphorylation, provides the STAT3 docking tyrosines. evidence: - source_id: PMID:16982608 statement: The ternary IL-10 signalling complex forms with IL-10:IL-10R1 first, then IL-10R2. supporting_text: >- The ternary IL-10 signaling complex is assembled in a sequential order with the IL-10.IL-10R1 interaction occurring first followed by engagement of the IL-10R2 chain. gocam_associations: - model: gomodel:626b20c100000681 activity: gomodel:626b20c100000681/626b20c100000689 title: IL10RA interleukin-10 receptor activity (GO:0004920), IL10-mediated signaling pathway (Human) - id: il10rb_coreceptor label: IL10RB shared second receptor chain participant: selector_type: GENE_PRODUCT gene_product: preferred_term: IL10RB term: id: UniProtKB:Q08334 label: Interleukin-10 receptor subunit beta function: preferred_term: coreceptor activity term: id: GO:0015026 label: coreceptor activity processes: - preferred_term: interleukin-10-mediated signaling pathway term: id: GO:0140105 label: interleukin-10-mediated signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Ubiquitously expressed low-affinity chain shared with the IL-22, IL-26 and type III interferon receptors; cannot bind IL-10 alone, joins the IL-10:IL10RA complex and brings TYK2. evidence: - source_id: PMID:9312047 statement: >- IL-10 binds IL-10R1 but does not signal without the second chain CRFB4 (IL-10R2), which is essential for the active receptor complex. supporting_text: >- serves as an accessory chain essential for the active IL-10 receptor complex and to initiate IL-10-induced signal transduction events gocam_associations: - model: gomodel:626b20c100000681 activity: gomodel:626b20c100000681/626b20c100000696 title: IL10RB coreceptor activity (GO:0015026), IL10-mediated signaling pathway (Human) - order: 2 role: JAK1 and TYK2 activation and IL10RA phosphorylation node: id: il10_jak1_tyk2_activation label: JAK1 and TYK2 activation and IL10RA tyrosine phosphorylation module_type: REGULATORY_STEP description: >- Ternary complex formation juxtaposes IL10RA-bound JAK1 and IL10RB-bound TYK2, which are tyrosine phosphorylated in response to IL-10 (JAK2 and JAK3 are not) and phosphorylate two tyrosines in the IL10RA cytoplasmic domain (murine Tyr427 and Tyr477), creating the STAT3 docking sites. JAK1 is required for the anti-inflammatory response. annotons: - id: jak1_kinase label: JAK1 tyrosine kinase (on IL10RA) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: JAK1 term: id: UniProtKB:P23458 label: Tyrosine-protein kinase JAK1 function: preferred_term: non-membrane spanning protein tyrosine kinase activity term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity processes: - preferred_term: interleukin-10-mediated signaling pathway term: id: GO:0140105 label: interleukin-10-mediated signaling pathway locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- IL10RA-associated Janus kinase that phosphorylates the receptor tail and STAT3; required for IL-10 inhibition of TNF production. evidence: - source_id: PMID:7543512 statement: IL-10 induces tyrosine phosphorylation of TYK2 and JAK1 but not JAK2 or JAK3. supporting_text: >- results in the ligand-induced tyrosine phosphorylation of tyk2 and Jak1, but not Jak2 or Jak3 - source_id: PMID:10347215 statement: IL-10 anti-inflammatory action needs STAT3, JAK1 and two IL10RA intracellular regions. supporting_text: >- requires the presence of Stat3, Jak1, and two distinct regions of the IL-10 receptor intracellular domain gocam_associations: - model: gomodel:626b20c100000681 activity: gomodel:626b20c100000681/626b20c100000712 title: JAK1 protein tyrosine kinase activity (GO:0004713), IL10-mediated signaling pathway (Human) - id: tyk2_kinase label: TYK2 tyrosine kinase (on IL10RB) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TYK2 term: id: UniProtKB:P29597 label: Non-receptor tyrosine-protein kinase TYK2 function: preferred_term: non-membrane spanning protein tyrosine kinase activity term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity processes: - preferred_term: interleukin-10-mediated signaling pathway term: id: GO:0140105 label: interleukin-10-mediated signaling pathway locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- IL10RB-associated Janus kinase brought into the complex with IL10RB; trans-activates with JAK1. evidence: - source_id: PMID:7543512 statement: TYK2 is tyrosine phosphorylated in response to IL-10 in T cells and monocytes. supporting_text: >- IL-10 treatment of both T cells and monocytes results in the ligand-induced tyrosine phosphorylation of tyk2 and Jak1 - source_id: file:genes/human/TYK2/TYK2-ai-review.yaml statement: >- The TYK2 gene review's core function is non-membrane spanning protein tyrosine kinase activity (GO:0004715) docked on cytokine receptor chains. gocam_associations: - model: gomodel:626b20c100000681 activity: gomodel:626b20c100000681/626b20c100000717 title: TYK2 protein tyrosine kinase activity (GO:0004713), IL10-mediated signaling pathway (Human) - order: 3 role: STAT3 docking and tyrosine phosphorylation node: id: il10_stat3_docking label: STAT3 docking on phospho-IL10RA and JAK phosphorylation module_type: REGULATORY_STEP description: >- STAT3 binds either of the two redundant phosphotyrosine motifs of IL10RA through its SH2 domain and is tyrosine phosphorylated by the receptor-associated JAKs. Only STAT3 is recruited this way. concepts: - preferred_term: tyrosine phosphorylation of STAT protein term: id: GO:0007260 label: tyrosine phosphorylation of STAT protein annotons: - id: stat3_transcription_factor label: STAT3 transcription factor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: STAT3 term: id: UniProtKB:P40763 label: Signal transducer and activator of transcription 3 function: preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific processes: - preferred_term: interleukin-10-mediated signaling pathway term: id: GO:0140105 label: interleukin-10-mediated signaling pathway locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: >- Recruited to phospho-IL10RA as JAK substrate; as a nuclear dimer it is the essential transcription factor of the IL-10 anti-inflammatory response. evidence: - source_id: PMID:8910398 statement: STAT3, but not STAT1 or STAT5, is recruited directly to phosphotyrosine sites of the IL-10 receptor. supporting_text: >- Stat3 but not Stat1 or Stat5 is directly recruited to the ligand-activated IL-10 receptor by binding to specific but redundant receptor intracellular domain sequences containing phosphotyrosine - source_id: file:genes/human/STAT3/STAT3-ai-review.yaml statement: >- The STAT3 gene review's core function is DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981). gocam_associations: - model: gomodel:626b20c100000681 activity: gomodel:626b20c100000681/626b20c100000721 title: STAT3 DNA-binding transcription factor activity (GO:0003700), IL10-mediated signaling pathway (Human) - order: 4 role: accessory STAT1 activation optional: true node: id: il10_stat1_activation label: Accessory STAT1 activation module_type: REGULATORY_STEP description: >- IL-10 also induces STAT1 tyrosine phosphorylation, forming STAT1 and STAT1:STAT3 complexes whose proportions differ between T cells and monocytes. STAT1 is not recruited through the STAT3 docking tyrosines and is not required for the anti-inflammatory response, so the step is optional. annotons: - id: stat1_transcription_factor label: STAT1 transcription factor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: STAT1 term: id: UniProtKB:P42224 label: Signal transducer and activator of transcription 1-alpha/beta function: preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific processes: - preferred_term: interleukin-10-mediated signaling pathway term: id: GO:0140105 label: interleukin-10-mediated signaling pathway locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: Minor, cell-type-dependent STAT activated by IL-10, partly as STAT1:STAT3 heterodimers. evidence: - source_id: PMID:7543512 statement: IL-10 stimulates tyrosine phosphorylation of STAT1 alpha and STAT3, differently in T cells and monocytes. supporting_text: >- IL-10 stimulates tyrosine phosphorylation of the signal transducers and activators of transcription, STAT1 alpha and STAT3, in a differential manner - order: 5 role: STAT dimerization and nuclear import node: id: il10_stat_dimerization_import label: STAT3 dimerization and nuclear import description: >- Included by reference to the generic STAT dimerization and karyopherin import step of the canonical JAK-STAT module. module_ref: jak_stat_signaling#stat_dimerization_import - order: 6 role: STAT3-dependent anti-inflammatory transcription node: id: il10_stat3_transcription label: STAT3-dependent anti-inflammatory transcription description: >- Included by reference to the STAT-dependent transcription step of the canonical JAK-STAT module. In IL-10-stimulated macrophages STAT3 induces transcriptional repressors and other mediators that suppress LPS-induced pro-inflammatory cytokine genes; SOCS3 is among the induced genes but is an output, not a regulator of this pathway (see notes). module_ref: jak_stat_signaling#stat_transcription evidence: - source_id: PMID:31611251 statement: SOCS3 is induced by both IL-10 and IL-6 in macrophages but suppresses only IL-6 receptor signalling. supporting_text: >- One such cofactor is the suppressor of cytokine signaling 3 (SOCS3), which, despite being induced by both IL-10 and IL-6 in macrophages, only suppresses the activity of the IL-6R connections: - source: il10_receptor_assembly target: il10_jak1_tyk2_activation connection_type: CAUSES description: Ternary complex assembly juxtaposes JAK1 and TYK2, which phosphorylate IL10RA. - source: il10_jak1_tyk2_activation target: il10_stat3_docking connection_type: CAUSES description: Phospho-IL10RA tyrosines recruit STAT3, which the JAKs phosphorylate. - source: il10_jak1_tyk2_activation target: il10_stat1_activation connection_type: CAUSES description: The activated receptor complex also phosphorylates STAT1, independently of the STAT3 docking sites. - source: il10_stat3_docking target: il10_stat_dimerization_import connection_type: PRECEDES description: Phospho-STAT3 leaves the receptor, dimerizes and enters the nucleus. - source: il10_stat_dimerization_import target: il10_stat3_transcription connection_type: PRECEDES description: Nuclear STAT3 dimers drive the anti-inflammatory gene programme. knowledge_gaps: - gap_statement: >- How the same activated STAT3 delivers an anti-inflammatory programme downstream of IL10RA but not downstream of gp130 is not fully explained: SOCS3 selectivity accounts for part of it, but the requirement for the serine-containing IL10RA C-terminal region and the STAT3 cofactors that make the programme IL-10-specific remain unidentified. gap_kind: - BIOLOGY