{"gene":"IL10RA","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2003,"finding":"Two specific tyrosine residues in the cytoplasmic domain of IL-10Rα (Tyr446 and Tyr496) are required for receptor function and for phosphorylation/activation of the downstream effector IL-10E1. Phosphorylated peptides encompassing these residues co-precipitated IL-10E1 and blocked ligand-dependent IL-10E1 phosphorylation, whereas serine substitutions at these positions abolished signaling. IL-10 triggers nuclear translocation of IL-10E1, dependent on these phosphotyrosines.","method":"In vitro phosphopeptide immunoprecipitation, site-directed mutagenesis (serine substitution), confocal microscopy of GFP-fusion proteins, cell-free signaling assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and multiple orthogonal methods (co-IP, functional blockade, live imaging) in a single rigorous study","pmids":["12802285"],"is_preprint":false},{"year":2016,"finding":"IL-10 inhibits starvation-induced autophagy in hypertrophic scar fibroblasts via two converging pathways downstream of IL-10Rα: (1) IL-10Rα-mediated activation of STAT3, and (2) direct activation of the AKT-mTOR pathway; mTOR-p70S6K is the convergence point. Blocking IL-10Rα with a specific inhibitor (IL10RB) abolished both STAT3 phosphorylation and AKT-mTOR activation and restored autophagy.","method":"Pharmacological inhibition of IL-10R, AKT, mTOR, and STAT3; Western blot for p-AKT, p-STAT3, p-mTOR; transmission electron microscopy for autophagy; dose-response assays in primary fibroblasts","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological inhibitors and orthogonal readouts in one study, single lab","pmids":["26962683"],"is_preprint":false},{"year":2016,"finding":"BCL6 directly represses the JAK2 promoter (confirmed by ChIP-seq) and suppresses surface IL-10Rα expression; loss of BCL6 leads to elevated IL-10Rα surface levels, increased JAK2 mRNA/protein, and STAT3 phosphorylation. Blockade of IL-10Rα in BCL6-deficient Burkitt lymphoma cells repressed STAT3 phosphorylation, placing IL-10Rα upstream of JAK2/STAT3 in this pathway.","method":"Synthetic lethal screen, conditional BCL6-deficient cell line, surface IL-10Rα measurement, IL-10Rα blockade + STAT3 phosphorylation readout, ChIP-seq","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal genetic and biochemical approaches (conditional KO, ChIP-seq, receptor blockade with functional readout) in a single rigorous study","pmids":["27268052"],"is_preprint":false},{"year":2012,"finding":"Type I interferons (IFN-α, IFN-β) and the type III interferon IL-29 upregulate IL-10R1 (IL-10Rα) surface expression on human monocytes and macrophages, increasing STAT3 phosphorylation in response to IL-10 and thereby enhancing IL-10-mediated suppression of TLR-induced IL-12p70 production.","method":"Flow cytometry for IL-10R1 surface expression, Western blot for pSTAT3, IFN priming followed by IL-10 stimulation and TLR-induced IL-12 measurement by ELISA in primary human monocytes/macrophages","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cytokines tested, orthogonal readouts (surface receptor, pSTAT3, cytokine output), single lab","pmids":["22685028"],"is_preprint":false},{"year":2020,"finding":"Aberrant upregulation of IL-10Rα expression in ALCL cells rewires STAT3 signaling, bypassing the normally required phosphorylation by NPM1-ALK, and thereby drives resistance to ALK inhibition by crizotinib. This was identified through genome-wide CRISPR activation and knockout screens combined with RNA-seq from relapsed patient tumors.","method":"Genome-wide CRISPR activation and knockout screens in ALCL cell lines; RNA sequencing of ALK inhibitor-relapsed patient tumors; functional validation of IL-10Rα-driven STAT3 signaling","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screens (both activation and KO), complemented by patient tumor RNA-seq, multiple orthogonal approaches","pmids":["32573700"],"is_preprint":false},{"year":2019,"finding":"The IL-10Rα missense variant p.Tyr91Cys fails to properly localize to the plasma membrane, likely due to disruption of a hydrophobic core structure around Tyr91, causing structural instability. Patient PBMCs with this variant showed defective STAT3 activation upon IL-10 stimulation.","method":"Flow cytometry for surface IL-10Rα expression, confocal microscopy of GFP-fused mutant proteins, computational structural modeling, STAT3 phosphorylation assay in patient PBMCs","journal":"Inflammatory bowel diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (STAT3 activation), multiple orthogonal methods, single lab","pmids":["30462267"],"is_preprint":false},{"year":2006,"finding":"IL-10Rα on SLE patient PBMCs signals normally through JAK-1, TYK-2, STAT-1, and STAT-3 phosphorylation, but IL-10R-dependent gene expression (cytokines, apoptosis, intracellular signaling) is aberrantly regulated in SLE patients compared to controls.","method":"Flow cytometry for IL-10R expression, Western blot for JAK-1/TYK-2/STAT-1/STAT-3 phosphorylation, cDNA microarray of 242 genes after IL-10 stimulation of patient PBMCs","journal":"Scandinavian journal of rheumatology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple orthogonal methods (Western blot kinetics, transcriptome), single lab, single study","pmids":["17062437"],"is_preprint":false},{"year":2024,"finding":"IL-10Rα expression on mesenchymal stem cells (MSCs) is required for IDO induction in co-culture with T cells: IL-10RA knockdown in MSCs significantly reduced IDO RNA, protein, and enzymatic activity, as well as STAT3 phosphorylation. This decreased T cell suppression and restored T cell cytotoxic killing of PDAC organoids.","method":"IL-10RA shRNA knockdown in primary MSCs, co-culture with T cells, STAT3 phosphorylation measurement, IDO activity assay, PDAC organoid killing assay","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple downstream readouts (STAT3, IDO expression, IDO activity, T cell function), single lab","pmids":["39592739"],"is_preprint":false},{"year":2025,"finding":"IL-10Rα overexpression in non-small cell lung cancer cells promotes proliferation by enhancing glycolysis and fatty acid oxidation (FAO) via activation of the STAT3 signaling pathway. STAT3 inhibition blocked the FAO increase and cell proliferation induced by IL-10Rα overexpression.","method":"IL-10RA overexpression and knockdown in NSCLC cell lines, cell proliferation assays, Seahorse metabolic flux assays for glycolysis and FAO, STAT3 inhibitor rescue experiments","journal":"Pulmonary pharmacology & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with metabolic readouts and pharmacological rescue, single lab","pmids":["39892560"],"is_preprint":false},{"year":2024,"finding":"IL-10/IL-10R/STAT3 axis signaling mediates M2-like polarization of tumor-associated macrophages in multiple myeloma bone marrow. Blocking IL-10Rα with a monoclonal antibody prevented M2 polarization and TAM-induced MM proliferation and drug resistance in vitro and in vivo.","method":"IL-10R monoclonal antibody blockade, STAT3 PROTAC degrader, 3D co-culture in vitro, patient BM samples, mouse xenograft models; M2/M1 macrophage phenotyping, MM proliferation and drug-sensitivity assays","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor blockade with defined functional phenotype in vitro and in vivo, multiple orthogonal methods, single lab","pmids":["39215060"],"is_preprint":false},{"year":2015,"finding":"BM-MSCs upregulate IL-10 secretion and the expression of its receptor CD210 (IL-10Rα) on co-cultured T cells, creating an autocrine/paracrine loop favoring expansion of IL-10-producing T cells. IL-10 neutralization restored T cell proliferation, demonstrating that the IL-10/IL-10Rα axis is functionally required for MSC-mediated T cell immunosuppression.","method":"Co-culture of T cells with BM-MSCs, IL-10 ELISA, flow cytometry for CD210/IL-10Rα surface expression, cell-trace proliferation assay, IL-10 neutralization rescue experiment, qPCR","journal":"Stem cell reviews and reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — neutralization rescue with multiple orthogonal readouts, single lab","pmids":["25326368"],"is_preprint":false},{"year":2025,"finding":"The hysteretic nonlinearity of IL-10R expression drives tumor-infiltrated immune cells into an IL-10Rhi state. Bacteria (engineered Salmonella) leverage elevated IL-10R expression to enhance IL-10 production by tumor-associated macrophages and enable phagocytosis evasion by tumor-associated neutrophils, while coincidently expanding exhausted tumor-resident CD8+ T cells.","method":"Engineered Salmonella enterica in murine tumor models, flow cytometry for IL-10R expression states, functional assays for macrophage IL-10 production and neutrophil phagocytosis, human sample analysis","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection in vivo with multiple cell types and functional readouts, single study","pmids":["40037354"],"is_preprint":false},{"year":2023,"finding":"IL-10RA knockout in bovine mammary epithelial cells (IL10RAKO MAC-T) infected with MAP led to greater secretion of pro-inflammatory cytokines (TNF-α, IL-6, IFN-γ, CCL3, CCL4, CXCL8, CXCL10) and loss of anti-inflammatory IL-10 and SOCS3 induction compared to wild-type cells, demonstrating that IL-10Rα mediates anti-inflammatory feedback during MAP infection. Additionally, miRNA responses (miR-133b, miR-92a, miR-184) induced by MAP infection in WT cells were absent in IL10RAKO cells.","method":"CRISPR-generated IL10RA knockout MAC-T cell line, MAP infection, multiplex immunoassay for cytokines/chemokines, qPCR for inflammatory genes and miRNAs","journal":"In vitro cellular & developmental biology. Animal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype and multiple molecular readouts, single lab","pmids":["37071310"],"is_preprint":false},{"year":2016,"finding":"A synonymous variant in IL10RA (p.T179T, c.537G>A) located before the 5' splice donor site causes exon skipping and out-of-frame fusion of exons 3 and 5, resulting in altered STAT3 phosphorylation in IL-10-induced PBMCs from patients with this mutation.","method":"Whole-exome and Sanger sequencing, RT-PCR to demonstrate aberrant splicing, STAT3 phosphorylation assay in patient PBMCs","journal":"Journal of Crohn's & colitis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct demonstration of splice error and downstream signaling defect in patient cells, single study","pmids":["27177777"],"is_preprint":false},{"year":2016,"finding":"A novel exonic mutation in IL10RA (c.537G>A, p.T179T) causes aberrant splicing resulting in loss of IL-10 receptor signaling (demonstrated by lack of STAT3 phosphorylation in patient PBMCs upon IL-10 stimulation).","method":"Sanger sequencing, RT-PCR for splice analysis, STAT3 phosphorylation assay in patient PBMCs","journal":"BMC gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional validation of splice defect with signaling readout in patient cells, single study; corroborates PMID 27177777","pmids":["26822028"],"is_preprint":false},{"year":2025,"finding":"IL-10R expression in the lung exhibits diurnal rhythmicity (circadian expression of Il10ra); blocking IL-10 signaling abrogated time-of-day-specific protection against influenza A virus, increasing immunopathology (enhanced lymphocyte infiltration, global immune activation). NK cell depletion suppressed IL-10 levels, suggesting NK cells regulate IL-10 signaling in the lung.","method":"IL-10R blockade in mice at different circadian times, transcriptomic analysis, NK cell depletion, BALF cytokine measurement, survival assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vivo pharmacological blockade with functional phenotype, preprint, single lab, no direct molecular dissection of IL-10Rα mechanism","pmids":["bio_10.1101_2025.03.03.641134"],"is_preprint":true},{"year":2024,"finding":"A non-coding SNP (rs4936415) in an IL10RA super-enhancer region regulates IL-10Rα expression: the protective G-allele promotes enhancer activity, while the risk C-allele specifically binds NF-κB1, which also promotes enhancer activity. BD patients show significantly lower serum IL-10Rα levels. This was established by ChIP, luciferase reporter assay, and EMSA.","method":"Chromatin immunoprecipitation (ChIP), luciferase gene-reporter assay, electrophoretic mobility shift assay (EMSA), ELISA for serum IL-10Rα levels, GWAS post-annotation bioinformatics","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods (ChIP, luciferase, EMSA) establishing regulatory mechanism, single lab","pmids":["39844988"],"is_preprint":false},{"year":2017,"finding":"IL-10R+ colonic macrophages and dendritic cells are more abundant in mice lacking type I IFN signaling (Ifnar1-/-) during Salmonella colitis; blockade of IL-10R in Ifnar1-/- mice increased susceptibility to S. typhimurium colitis, demonstrating a cross-regulatory interaction in which type I IFN restrains immunoregulatory IL-10R-expressing myeloid cells and that their IL-10 signaling is protective.","method":"Ifnar1-/- mouse model, IL-10R blockade (anti-IL-10R mAb), flow cytometry for macrophage/DC subsets and IL-10R expression, survival and colitis severity scoring","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus pharmacological receptor blockade with defined in vivo phenotype, single lab","pmids":["29190678"],"is_preprint":false},{"year":2023,"finding":"Downregulation of IL-10R expression in dendritic cells (via lentiviral shRNA) enhances their ability to activate anti-tumor immune responses in vitro and, combined with HES-MTX nanoconjugate, leads to greatest tumor growth inhibition in MC38 murine colon carcinoma in vivo, with decreased suppressor cell infiltration and increased effector cell infiltration in tumors.","method":"Lentiviral shRNA knockdown of IL-10R in DCs, in vivo tumor model (MC38), flow cytometry of tumor-infiltrating immune cells, ELISA, tumor volume monitoring","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function in defined cell type with in vitro and in vivo functional readouts, single lab","pmids":["37033926"],"is_preprint":false}],"current_model":"IL-10Rα (IL10RA) is the ligand-binding alpha subunit of the heterodimeric IL-10 receptor; upon IL-10 binding, specific cytoplasmic tyrosine residues (Tyr446, Tyr496) are phosphorylated, recruiting downstream effectors and activating the JAK1/TYK2-STAT3 signaling axis, which mediates anti-inflammatory gene expression, suppression of TLR-induced IL-12, inhibition of autophagy via AKT-mTOR and STAT3, and induction of IDO in stromal cells; loss-of-function mutations (missense, splice-site, frameshift, or large deletions) in IL10RA abrogate STAT3 phosphorylation and cause severe very-early-onset inflammatory bowel disease, while aberrant upregulation of IL-10Rα in malignant cells rewires STAT3 signaling to promote drug resistance and tumor survival."},"narrative":{"mechanistic_narrative":"IL10RA encodes the ligand-binding alpha subunit of the IL-10 receptor that transduces anti-inflammatory IL-10 signals through the JAK/STAT3 axis to restrain inflammation [PMID:12802285, PMID:27268052, PMID:37071310]. Upon ligand engagement, specific cytoplasmic phosphotyrosines (Tyr446 and Tyr496) are required for receptor function and recruit downstream effectors, with serine substitution at these positions abolishing signaling [PMID:12802285], and the receptor acts upstream of JAK2/STAT3 to drive STAT3 phosphorylation [PMID:27268052]. Functionally, IL-10Rα-dependent signaling enforces anti-inflammatory feedback: its loss derepresses pro-inflammatory cytokine/chemokine secretion and abrogates IL-10/SOCS3 induction during infection [PMID:37071310], and in myeloid cells it mediates IL-10 suppression of TLR-induced IL-12 [PMID:22685028]. Loss-of-function changes in IL10RA—a missense variant (p.Tyr91Cys) that disrupts plasma-membrane localization and a synonymous splice-disrupting variant (p.T179T) causing exon skipping—each abolish IL-10-induced STAT3 phosphorylation in patient cells, establishing IL10RA defects as a cause of receptor signaling failure [PMID:30462267, PMID:27177777, PMID:26822028]. Receptor abundance is set by transcriptional and enhancer-level control: BCL6 represses surface IL-10Rα via the JAK2 promoter [PMID:27268052], type I/III interferons upregulate surface IL-10Rα to amplify STAT3 responses [PMID:22685028], and a super-enhancer SNP (rs4936415) tunes expression through NF-κB1 binding [PMID:39844988]. In cancer, aberrant IL-10Rα upregulation rewires STAT3 signaling to drive crizotinib resistance in ALCL by bypassing NPM1-ALK [PMID:32573700], and IL-10Rα-driven STAT3 activity promotes tumor-cell metabolism and proliferation [PMID:39892560], M2-like tumor-associated macrophage polarization [PMID:39215060], and stromal IDO induction with T-cell suppression [PMID:39592739].","teleology":[{"year":2003,"claim":"Established which cytoplasmic determinants of IL-10Rα are required for signal transduction, defining how the receptor engages downstream effectors.","evidence":"In vitro phosphopeptide co-IP, serine-substitution mutagenesis, and confocal imaging of GFP fusions in cell-free signaling assays","pmids":["12802285"],"confidence":"High","gaps":["Did not place these phosphotyrosines within the full JAK1/TYK2-STAT3 cascade","Identity and generality of the IL-10E1 effector across cell types not resolved"]},{"year":2006,"claim":"Tested whether IL-10Rα proximal signaling is intact in autoimmune disease, distinguishing receptor-level defects from downstream transcriptional dysregulation.","evidence":"Flow cytometry, Western blot kinetics for JAK1/TYK2/STAT1/STAT3, and cDNA microarray of IL-10-stimulated SLE patient PBMCs","pmids":["17062437"],"confidence":"Medium","gaps":["Mechanism of aberrant gene-expression regulation downstream of normal phosphorylation not identified","Correlative patient comparison without causal manipulation"]},{"year":2012,"claim":"Showed that receptor abundance is a tunable control point, with interferons priming IL-10Rα surface levels to amplify anti-inflammatory output.","evidence":"IFN priming followed by IL-10 stimulation with surface-receptor flow cytometry, pSTAT3 Western blot, and TLR-induced IL-12 ELISA in primary human myeloid cells","pmids":["22685028"],"confidence":"Medium","gaps":["Transcriptional mechanism of IFN-driven IL-10Rα upregulation not defined","Single-lab primary cell study"]},{"year":2016,"claim":"Identified transcriptional repression of receptor/kinase expression by BCL6 and a converging autophagy-suppressive role, refining how IL-10Rα output is set and what it controls.","evidence":"Conditional BCL6-KO with ChIP-seq and receptor blockade (lymphoma); pharmacological IL-10R/AKT/mTOR/STAT3 inhibition with autophagy readouts in fibroblasts","pmids":["27268052","26962683"],"confidence":"High","gaps":["Direct biochemical link between IL-10Rα engagement and AKT-mTOR activation not resolved","Generality of BCL6-IL-10Rα axis beyond lymphoma cells unknown"]},{"year":2016,"claim":"Defined a disease-causing splicing mechanism, showing a synonymous coding variant abolishes receptor signaling in patients with very-early-onset intestinal inflammation.","evidence":"Exome/Sanger sequencing, RT-PCR demonstrating exon skipping, and STAT3 phosphorylation assays in patient PBMCs (two independent reports)","pmids":["27177777","26822028"],"confidence":"Medium","gaps":["Quantitative residual receptor function not measured","No in vivo or organoid rescue of the splicing defect"]},{"year":2019,"claim":"Demonstrated that a missense variant disrupts receptor trafficking, linking structural instability to failed surface localization and signaling loss.","evidence":"Surface-expression flow cytometry, confocal imaging of GFP-fused mutants, structural modeling, and STAT3 phosphorylation in patient PBMCs","pmids":["30462267"],"confidence":"Medium","gaps":["Trafficking/degradation route of the mislocalized mutant not defined","Structural disruption inferred computationally, not solved experimentally"]},{"year":2020,"claim":"Revealed that pathological IL-10Rα upregulation rewires STAT3 to bypass oncogenic kinase dependence, driving targeted-therapy resistance.","evidence":"Genome-wide CRISPR activation and knockout screens in ALCL lines plus RNA-seq of crizotinib-relapsed patient tumors","pmids":["32573700"],"confidence":"High","gaps":["Upstream trigger of aberrant IL-10Rα induction in resistant tumors not defined","Whether ligand-independent or IL-10-driven signaling sustains resistance unclear"]},{"year":2024,"claim":"Extended IL-10Rα function to stromal immunosuppression, showing receptor expression is required for IDO induction and T-cell suppression in the tumor microenvironment.","evidence":"shRNA IL10RA knockdown in primary MSCs with STAT3, IDO expression/activity, and PDAC organoid killing readouts; BM-MSC/T-cell co-culture with IL-10 neutralization","pmids":["39592739","25326368"],"confidence":"Medium","gaps":["Direct STAT3-to-IDO transcriptional link not biochemically mapped","In vitro co-culture systems without in vivo confirmation"]},{"year":2024,"claim":"Established IL-10Rα as a regulatory node setting receptor-expression states and myeloid behavior across tissue and tumor contexts.","evidence":"Super-enhancer SNP analysis (ChIP, luciferase, EMSA) for NF-κB1-dependent expression; IL-10R blockade and shRNA in myeloid/DC models in vitro and in vivo; type I IFN cross-regulation in Ifnar1-/- colitis","pmids":["39844988","39215060","37033926","29190678"],"confidence":"Medium","gaps":["Cell-type-specific transcriptional control of IL-10Rα incompletely mapped","Causal contribution of receptor-expression hysteresis to in vivo outcomes inferred indirectly"]},{"year":2025,"claim":"Probed dynamic and context-dependent regulation of IL-10R expression states governing tumor immune evasion, metabolism, and circadian antiviral protection.","evidence":"Engineered Salmonella tumor models, IL-10Rα overexpression/knockdown with Seahorse metabolic flux, and circadian IL-10R blockade in influenza models (one preprint)","pmids":["40037354","39892560","bio_10.1101_2025.03.03.641134"],"confidence":"Medium","gaps":["Molecular basis of IL-10R expression hysteresis not defined","Circadian regulation evidence is a single preprint lacking molecular dissection of IL-10Rα"]},{"year":null,"claim":"How IL-10Rα proximal phosphotyrosine signaling is mechanistically coupled to both STAT3 and the AKT-mTOR branch, and what governs the switch-like control of receptor surface abundance across cell types, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the assembled ligand-bound receptor complex in the corpus","Direct biochemical bridge from IL-10Rα to AKT-mTOR not established","Unified mechanism linking receptor-expression state to functional output not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3,5,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,12,17]}],"complexes":["IL-10 receptor"],"partners":["IL10","JAK2","STAT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13651","full_name":"Interleukin-10 receptor subunit alpha","aliases":["CDw210a","Interleukin-10 receptor subunit 1","IL-10R subunit 1","IL-10R1"],"length_aa":578,"mass_kda":63.0,"function":"Cell surface receptor for the cytokine IL10 that participates in IL10-mediated anti-inflammatory functions, limiting excessive tissue disruption caused by inflammation. Upon binding to IL10, induces a conformational change in IL10RB, allowing IL10RB to bind IL10 as well (PubMed:16982608). In turn, the heterotetrameric assembly complex, composed of two subunits of IL10RA and IL10RB, activates the kinases JAK1 and TYK2 that are constitutively associated with IL10RA and IL10RB respectively (PubMed:12133952). These kinases then phosphorylate specific tyrosine residues in the intracellular domain in IL10RA leading to the recruitment and subsequent phosphorylation of STAT3. Once phosphorylated, STAT3 homodimerizes, translocates to the nucleus and activates the expression of anti-inflammatory genes. In addition, IL10RA-mediated activation of STAT3 inhibits starvation-induced autophagy (PubMed:26962683)","subcellular_location":"Cell membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q13651/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL10RA","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL10RA","total_profiled":1310},"omim":[{"mim_id":"613148","title":"INFLAMMATORY BOWEL DISEASE 28, AUTOSOMAL RECESSIVE; IBD28","url":"https://www.omim.org/entry/613148"},{"mim_id":"612567","title":"INFLAMMATORY BOWEL DISEASE 25, AUTOSOMAL RECESSIVE; IBD25","url":"https://www.omim.org/entry/612567"},{"mim_id":"605687","title":"INTERLEUKIN 19; IL19","url":"https://www.omim.org/entry/605687"},{"mim_id":"605457","title":"INTERLEUKIN 22 RECEPTOR, ALPHA-1; IL22RA1","url":"https://www.omim.org/entry/605457"},{"mim_id":"605330","title":"INTERLEUKIN 22; IL22","url":"https://www.omim.org/entry/605330"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Primary cilium","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":54.5},{"tissue":"lymphoid tissue","ntpm":71.6}],"url":"https://www.proteinatlas.org/search/IL10RA"},"hgnc":{"alias_symbol":["HIL-10R","CDW210A","CD210a","CD210"],"prev_symbol":["IL10R"]},"alphafold":{"accession":"Q13651","domains":[{"cath_id":"2.60.40.10","chopping":"32-123","consensus_level":"high","plddt":95.5178,"start":32,"end":123},{"cath_id":"2.60.40.10","chopping":"130-230","consensus_level":"high","plddt":92.3384,"start":130,"end":230}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13651","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13651-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13651-F1-predicted_aligned_error_v6.png","plddt_mean":62.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL10RA","jax_strain_url":"https://www.jax.org/strain/search?query=IL10RA"},"sequence":{"accession":"Q13651","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13651.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13651/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13651"}},"corpus_meta":[{"pmid":"22550014","id":"PMC_22550014","title":"IL-10R polymorphisms are associated with very-early-onset ulcerative colitis.","date":"2013","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/22550014","citation_count":194,"is_preprint":false},{"pmid":"10939619","id":"PMC_10939619","title":"Comparative quantification of IL-1beta, IL-10, IL-10r, TNFalpha and IL-7 mRNA levels in UV-irradiated human skin in vivo.","date":"2000","source":"Inflammation research : official journal of the European Histamine Research Society ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/10939619","citation_count":110,"is_preprint":false},{"pmid":"24089328","id":"PMC_24089328","title":"A Mendelian predisposition to B-cell lymphoma caused by IL-10R deficiency.","date":"2013","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/24089328","citation_count":109,"is_preprint":false},{"pmid":"26962683","id":"PMC_26962683","title":"IL10 inhibits starvation-induced autophagy in hypertrophic scar fibroblasts via cross talk between the IL10-IL10R-STAT3 and IL10-AKT-mTOR pathways.","date":"2016","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/26962683","citation_count":68,"is_preprint":false},{"pmid":"40037354","id":"PMC_40037354","title":"Bacterial immunotherapy leveraging IL-10R hysteresis for both phagocytosis evasion and tumor immunity 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Phosphorylated peptides encompassing these residues co-precipitated IL-10E1 and blocked ligand-dependent IL-10E1 phosphorylation, whereas serine substitutions at these positions abolished signaling. IL-10 triggers nuclear translocation of IL-10E1, dependent on these phosphotyrosines.\",\n      \"method\": \"In vitro phosphopeptide immunoprecipitation, site-directed mutagenesis (serine substitution), confocal microscopy of GFP-fusion proteins, cell-free signaling assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and multiple orthogonal methods (co-IP, functional blockade, live imaging) in a single rigorous study\",\n      \"pmids\": [\"12802285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-10 inhibits starvation-induced autophagy in hypertrophic scar fibroblasts via two converging pathways downstream of IL-10Rα: (1) IL-10Rα-mediated activation of STAT3, and (2) direct activation of the AKT-mTOR pathway; mTOR-p70S6K is the convergence point. Blocking IL-10Rα with a specific inhibitor (IL10RB) abolished both STAT3 phosphorylation and AKT-mTOR activation and restored autophagy.\",\n      \"method\": \"Pharmacological inhibition of IL-10R, AKT, mTOR, and STAT3; Western blot for p-AKT, p-STAT3, p-mTOR; transmission electron microscopy for autophagy; dose-response assays in primary fibroblasts\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological inhibitors and orthogonal readouts in one study, single lab\",\n      \"pmids\": [\"26962683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BCL6 directly represses the JAK2 promoter (confirmed by ChIP-seq) and suppresses surface IL-10Rα expression; loss of BCL6 leads to elevated IL-10Rα surface levels, increased JAK2 mRNA/protein, and STAT3 phosphorylation. Blockade of IL-10Rα in BCL6-deficient Burkitt lymphoma cells repressed STAT3 phosphorylation, placing IL-10Rα upstream of JAK2/STAT3 in this pathway.\",\n      \"method\": \"Synthetic lethal screen, conditional BCL6-deficient cell line, surface IL-10Rα measurement, IL-10Rα blockade + STAT3 phosphorylation readout, ChIP-seq\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal genetic and biochemical approaches (conditional KO, ChIP-seq, receptor blockade with functional readout) in a single rigorous study\",\n      \"pmids\": [\"27268052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Type I interferons (IFN-α, IFN-β) and the type III interferon IL-29 upregulate IL-10R1 (IL-10Rα) surface expression on human monocytes and macrophages, increasing STAT3 phosphorylation in response to IL-10 and thereby enhancing IL-10-mediated suppression of TLR-induced IL-12p70 production.\",\n      \"method\": \"Flow cytometry for IL-10R1 surface expression, Western blot for pSTAT3, IFN priming followed by IL-10 stimulation and TLR-induced IL-12 measurement by ELISA in primary human monocytes/macrophages\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cytokines tested, orthogonal readouts (surface receptor, pSTAT3, cytokine output), single lab\",\n      \"pmids\": [\"22685028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Aberrant upregulation of IL-10Rα expression in ALCL cells rewires STAT3 signaling, bypassing the normally required phosphorylation by NPM1-ALK, and thereby drives resistance to ALK inhibition by crizotinib. This was identified through genome-wide CRISPR activation and knockout screens combined with RNA-seq from relapsed patient tumors.\",\n      \"method\": \"Genome-wide CRISPR activation and knockout screens in ALCL cell lines; RNA sequencing of ALK inhibitor-relapsed patient tumors; functional validation of IL-10Rα-driven STAT3 signaling\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screens (both activation and KO), complemented by patient tumor RNA-seq, multiple orthogonal approaches\",\n      \"pmids\": [\"32573700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The IL-10Rα missense variant p.Tyr91Cys fails to properly localize to the plasma membrane, likely due to disruption of a hydrophobic core structure around Tyr91, causing structural instability. Patient PBMCs with this variant showed defective STAT3 activation upon IL-10 stimulation.\",\n      \"method\": \"Flow cytometry for surface IL-10Rα expression, confocal microscopy of GFP-fused mutant proteins, computational structural modeling, STAT3 phosphorylation assay in patient PBMCs\",\n      \"journal\": \"Inflammatory bowel diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (STAT3 activation), multiple orthogonal methods, single lab\",\n      \"pmids\": [\"30462267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-10Rα on SLE patient PBMCs signals normally through JAK-1, TYK-2, STAT-1, and STAT-3 phosphorylation, but IL-10R-dependent gene expression (cytokines, apoptosis, intracellular signaling) is aberrantly regulated in SLE patients compared to controls.\",\n      \"method\": \"Flow cytometry for IL-10R expression, Western blot for JAK-1/TYK-2/STAT-1/STAT-3 phosphorylation, cDNA microarray of 242 genes after IL-10 stimulation of patient PBMCs\",\n      \"journal\": \"Scandinavian journal of rheumatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple orthogonal methods (Western blot kinetics, transcriptome), single lab, single study\",\n      \"pmids\": [\"17062437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-10Rα expression on mesenchymal stem cells (MSCs) is required for IDO induction in co-culture with T cells: IL-10RA knockdown in MSCs significantly reduced IDO RNA, protein, and enzymatic activity, as well as STAT3 phosphorylation. This decreased T cell suppression and restored T cell cytotoxic killing of PDAC organoids.\",\n      \"method\": \"IL-10RA shRNA knockdown in primary MSCs, co-culture with T cells, STAT3 phosphorylation measurement, IDO activity assay, PDAC organoid killing assay\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple downstream readouts (STAT3, IDO expression, IDO activity, T cell function), single lab\",\n      \"pmids\": [\"39592739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-10Rα overexpression in non-small cell lung cancer cells promotes proliferation by enhancing glycolysis and fatty acid oxidation (FAO) via activation of the STAT3 signaling pathway. STAT3 inhibition blocked the FAO increase and cell proliferation induced by IL-10Rα overexpression.\",\n      \"method\": \"IL-10RA overexpression and knockdown in NSCLC cell lines, cell proliferation assays, Seahorse metabolic flux assays for glycolysis and FAO, STAT3 inhibitor rescue experiments\",\n      \"journal\": \"Pulmonary pharmacology & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with metabolic readouts and pharmacological rescue, single lab\",\n      \"pmids\": [\"39892560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-10/IL-10R/STAT3 axis signaling mediates M2-like polarization of tumor-associated macrophages in multiple myeloma bone marrow. Blocking IL-10Rα with a monoclonal antibody prevented M2 polarization and TAM-induced MM proliferation and drug resistance in vitro and in vivo.\",\n      \"method\": \"IL-10R monoclonal antibody blockade, STAT3 PROTAC degrader, 3D co-culture in vitro, patient BM samples, mouse xenograft models; M2/M1 macrophage phenotyping, MM proliferation and drug-sensitivity assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor blockade with defined functional phenotype in vitro and in vivo, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"39215060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BM-MSCs upregulate IL-10 secretion and the expression of its receptor CD210 (IL-10Rα) on co-cultured T cells, creating an autocrine/paracrine loop favoring expansion of IL-10-producing T cells. IL-10 neutralization restored T cell proliferation, demonstrating that the IL-10/IL-10Rα axis is functionally required for MSC-mediated T cell immunosuppression.\",\n      \"method\": \"Co-culture of T cells with BM-MSCs, IL-10 ELISA, flow cytometry for CD210/IL-10Rα surface expression, cell-trace proliferation assay, IL-10 neutralization rescue experiment, qPCR\",\n      \"journal\": \"Stem cell reviews and reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — neutralization rescue with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"25326368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The hysteretic nonlinearity of IL-10R expression drives tumor-infiltrated immune cells into an IL-10Rhi state. Bacteria (engineered Salmonella) leverage elevated IL-10R expression to enhance IL-10 production by tumor-associated macrophages and enable phagocytosis evasion by tumor-associated neutrophils, while coincidently expanding exhausted tumor-resident CD8+ T cells.\",\n      \"method\": \"Engineered Salmonella enterica in murine tumor models, flow cytometry for IL-10R expression states, functional assays for macrophage IL-10 production and neutrophil phagocytosis, human sample analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection in vivo with multiple cell types and functional readouts, single study\",\n      \"pmids\": [\"40037354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-10RA knockout in bovine mammary epithelial cells (IL10RAKO MAC-T) infected with MAP led to greater secretion of pro-inflammatory cytokines (TNF-α, IL-6, IFN-γ, CCL3, CCL4, CXCL8, CXCL10) and loss of anti-inflammatory IL-10 and SOCS3 induction compared to wild-type cells, demonstrating that IL-10Rα mediates anti-inflammatory feedback during MAP infection. Additionally, miRNA responses (miR-133b, miR-92a, miR-184) induced by MAP infection in WT cells were absent in IL10RAKO cells.\",\n      \"method\": \"CRISPR-generated IL10RA knockout MAC-T cell line, MAP infection, multiplex immunoassay for cytokines/chemokines, qPCR for inflammatory genes and miRNAs\",\n      \"journal\": \"In vitro cellular & developmental biology. Animal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype and multiple molecular readouts, single lab\",\n      \"pmids\": [\"37071310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A synonymous variant in IL10RA (p.T179T, c.537G>A) located before the 5' splice donor site causes exon skipping and out-of-frame fusion of exons 3 and 5, resulting in altered STAT3 phosphorylation in IL-10-induced PBMCs from patients with this mutation.\",\n      \"method\": \"Whole-exome and Sanger sequencing, RT-PCR to demonstrate aberrant splicing, STAT3 phosphorylation assay in patient PBMCs\",\n      \"journal\": \"Journal of Crohn's & colitis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct demonstration of splice error and downstream signaling defect in patient cells, single study\",\n      \"pmids\": [\"27177777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A novel exonic mutation in IL10RA (c.537G>A, p.T179T) causes aberrant splicing resulting in loss of IL-10 receptor signaling (demonstrated by lack of STAT3 phosphorylation in patient PBMCs upon IL-10 stimulation).\",\n      \"method\": \"Sanger sequencing, RT-PCR for splice analysis, STAT3 phosphorylation assay in patient PBMCs\",\n      \"journal\": \"BMC gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional validation of splice defect with signaling readout in patient cells, single study; corroborates PMID 27177777\",\n      \"pmids\": [\"26822028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-10R expression in the lung exhibits diurnal rhythmicity (circadian expression of Il10ra); blocking IL-10 signaling abrogated time-of-day-specific protection against influenza A virus, increasing immunopathology (enhanced lymphocyte infiltration, global immune activation). NK cell depletion suppressed IL-10 levels, suggesting NK cells regulate IL-10 signaling in the lung.\",\n      \"method\": \"IL-10R blockade in mice at different circadian times, transcriptomic analysis, NK cell depletion, BALF cytokine measurement, survival assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vivo pharmacological blockade with functional phenotype, preprint, single lab, no direct molecular dissection of IL-10Rα mechanism\",\n      \"pmids\": [\"bio_10.1101_2025.03.03.641134\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A non-coding SNP (rs4936415) in an IL10RA super-enhancer region regulates IL-10Rα expression: the protective G-allele promotes enhancer activity, while the risk C-allele specifically binds NF-κB1, which also promotes enhancer activity. BD patients show significantly lower serum IL-10Rα levels. This was established by ChIP, luciferase reporter assay, and EMSA.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase gene-reporter assay, electrophoretic mobility shift assay (EMSA), ELISA for serum IL-10Rα levels, GWAS post-annotation bioinformatics\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods (ChIP, luciferase, EMSA) establishing regulatory mechanism, single lab\",\n      \"pmids\": [\"39844988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-10R+ colonic macrophages and dendritic cells are more abundant in mice lacking type I IFN signaling (Ifnar1-/-) during Salmonella colitis; blockade of IL-10R in Ifnar1-/- mice increased susceptibility to S. typhimurium colitis, demonstrating a cross-regulatory interaction in which type I IFN restrains immunoregulatory IL-10R-expressing myeloid cells and that their IL-10 signaling is protective.\",\n      \"method\": \"Ifnar1-/- mouse model, IL-10R blockade (anti-IL-10R mAb), flow cytometry for macrophage/DC subsets and IL-10R expression, survival and colitis severity scoring\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus pharmacological receptor blockade with defined in vivo phenotype, single lab\",\n      \"pmids\": [\"29190678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Downregulation of IL-10R expression in dendritic cells (via lentiviral shRNA) enhances their ability to activate anti-tumor immune responses in vitro and, combined with HES-MTX nanoconjugate, leads to greatest tumor growth inhibition in MC38 murine colon carcinoma in vivo, with decreased suppressor cell infiltration and increased effector cell infiltration in tumors.\",\n      \"method\": \"Lentiviral shRNA knockdown of IL-10R in DCs, in vivo tumor model (MC38), flow cytometry of tumor-infiltrating immune cells, ELISA, tumor volume monitoring\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function in defined cell type with in vitro and in vivo functional readouts, single lab\",\n      \"pmids\": [\"37033926\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-10Rα (IL10RA) is the ligand-binding alpha subunit of the heterodimeric IL-10 receptor; upon IL-10 binding, specific cytoplasmic tyrosine residues (Tyr446, Tyr496) are phosphorylated, recruiting downstream effectors and activating the JAK1/TYK2-STAT3 signaling axis, which mediates anti-inflammatory gene expression, suppression of TLR-induced IL-12, inhibition of autophagy via AKT-mTOR and STAT3, and induction of IDO in stromal cells; loss-of-function mutations (missense, splice-site, frameshift, or large deletions) in IL10RA abrogate STAT3 phosphorylation and cause severe very-early-onset inflammatory bowel disease, while aberrant upregulation of IL-10Rα in malignant cells rewires STAT3 signaling to promote drug resistance and tumor survival.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL10RA encodes the ligand-binding alpha subunit of the IL-10 receptor that transduces anti-inflammatory IL-10 signals through the JAK/STAT3 axis to restrain inflammation [#0, #2, #12]. Upon ligand engagement, specific cytoplasmic phosphotyrosines (Tyr446 and Tyr496) are required for receptor function and recruit downstream effectors, with serine substitution at these positions abolishing signaling [#0], and the receptor acts upstream of JAK2/STAT3 to drive STAT3 phosphorylation [#2]. Functionally, IL-10Rα-dependent signaling enforces anti-inflammatory feedback: its loss derepresses pro-inflammatory cytokine/chemokine secretion and abrogates IL-10/SOCS3 induction during infection [#12], and in myeloid cells it mediates IL-10 suppression of TLR-induced IL-12 [#3]. Loss-of-function changes in IL10RA—a missense variant (p.Tyr91Cys) that disrupts plasma-membrane localization and a synonymous splice-disrupting variant (p.T179T) causing exon skipping—each abolish IL-10-induced STAT3 phosphorylation in patient cells, establishing IL10RA defects as a cause of receptor signaling failure [#5, #13, #14]. Receptor abundance is set by transcriptional and enhancer-level control: BCL6 represses surface IL-10Rα via the JAK2 promoter [#2], type I/III interferons upregulate surface IL-10Rα to amplify STAT3 responses [#3], and a super-enhancer SNP (rs4936415) tunes expression through NF-κB1 binding [#16]. In cancer, aberrant IL-10Rα upregulation rewires STAT3 signaling to drive crizotinib resistance in ALCL by bypassing NPM1-ALK [#4], and IL-10Rα-driven STAT3 activity promotes tumor-cell metabolism and proliferation [#8], M2-like tumor-associated macrophage polarization [#9], and stromal IDO induction with T-cell suppression [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established which cytoplasmic determinants of IL-10Rα are required for signal transduction, defining how the receptor engages downstream effectors.\",\n      \"evidence\": \"In vitro phosphopeptide co-IP, serine-substitution mutagenesis, and confocal imaging of GFP fusions in cell-free signaling assays\",\n      \"pmids\": [\"12802285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not place these phosphotyrosines within the full JAK1/TYK2-STAT3 cascade\", \"Identity and generality of the IL-10E1 effector across cell types not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Tested whether IL-10Rα proximal signaling is intact in autoimmune disease, distinguishing receptor-level defects from downstream transcriptional dysregulation.\",\n      \"evidence\": \"Flow cytometry, Western blot kinetics for JAK1/TYK2/STAT1/STAT3, and cDNA microarray of IL-10-stimulated SLE patient PBMCs\",\n      \"pmids\": [\"17062437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of aberrant gene-expression regulation downstream of normal phosphorylation not identified\", \"Correlative patient comparison without causal manipulation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed that receptor abundance is a tunable control point, with interferons priming IL-10Rα surface levels to amplify anti-inflammatory output.\",\n      \"evidence\": \"IFN priming followed by IL-10 stimulation with surface-receptor flow cytometry, pSTAT3 Western blot, and TLR-induced IL-12 ELISA in primary human myeloid cells\",\n      \"pmids\": [\"22685028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional mechanism of IFN-driven IL-10Rα upregulation not defined\", \"Single-lab primary cell study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified transcriptional repression of receptor/kinase expression by BCL6 and a converging autophagy-suppressive role, refining how IL-10Rα output is set and what it controls.\",\n      \"evidence\": \"Conditional BCL6-KO with ChIP-seq and receptor blockade (lymphoma); pharmacological IL-10R/AKT/mTOR/STAT3 inhibition with autophagy readouts in fibroblasts\",\n      \"pmids\": [\"27268052\", \"26962683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between IL-10Rα engagement and AKT-mTOR activation not resolved\", \"Generality of BCL6-IL-10Rα axis beyond lymphoma cells unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a disease-causing splicing mechanism, showing a synonymous coding variant abolishes receptor signaling in patients with very-early-onset intestinal inflammation.\",\n      \"evidence\": \"Exome/Sanger sequencing, RT-PCR demonstrating exon skipping, and STAT3 phosphorylation assays in patient PBMCs (two independent reports)\",\n      \"pmids\": [\"27177777\", \"26822028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative residual receptor function not measured\", \"No in vivo or organoid rescue of the splicing defect\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that a missense variant disrupts receptor trafficking, linking structural instability to failed surface localization and signaling loss.\",\n      \"evidence\": \"Surface-expression flow cytometry, confocal imaging of GFP-fused mutants, structural modeling, and STAT3 phosphorylation in patient PBMCs\",\n      \"pmids\": [\"30462267\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trafficking/degradation route of the mislocalized mutant not defined\", \"Structural disruption inferred computationally, not solved experimentally\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed that pathological IL-10Rα upregulation rewires STAT3 to bypass oncogenic kinase dependence, driving targeted-therapy resistance.\",\n      \"evidence\": \"Genome-wide CRISPR activation and knockout screens in ALCL lines plus RNA-seq of crizotinib-relapsed patient tumors\",\n      \"pmids\": [\"32573700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream trigger of aberrant IL-10Rα induction in resistant tumors not defined\", \"Whether ligand-independent or IL-10-driven signaling sustains resistance unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended IL-10Rα function to stromal immunosuppression, showing receptor expression is required for IDO induction and T-cell suppression in the tumor microenvironment.\",\n      \"evidence\": \"shRNA IL10RA knockdown in primary MSCs with STAT3, IDO expression/activity, and PDAC organoid killing readouts; BM-MSC/T-cell co-culture with IL-10 neutralization\",\n      \"pmids\": [\"39592739\", \"25326368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct STAT3-to-IDO transcriptional link not biochemically mapped\", \"In vitro co-culture systems without in vivo confirmation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established IL-10Rα as a regulatory node setting receptor-expression states and myeloid behavior across tissue and tumor contexts.\",\n      \"evidence\": \"Super-enhancer SNP analysis (ChIP, luciferase, EMSA) for NF-κB1-dependent expression; IL-10R blockade and shRNA in myeloid/DC models in vitro and in vivo; type I IFN cross-regulation in Ifnar1-/- colitis\",\n      \"pmids\": [\"39844988\", \"39215060\", \"37033926\", \"29190678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type-specific transcriptional control of IL-10Rα incompletely mapped\", \"Causal contribution of receptor-expression hysteresis to in vivo outcomes inferred indirectly\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Probed dynamic and context-dependent regulation of IL-10R expression states governing tumor immune evasion, metabolism, and circadian antiviral protection.\",\n      \"evidence\": \"Engineered Salmonella tumor models, IL-10Rα overexpression/knockdown with Seahorse metabolic flux, and circadian IL-10R blockade in influenza models (one preprint)\",\n      \"pmids\": [\"40037354\", \"39892560\", \"bio_10.1101_2025.03.03.641134\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of IL-10R expression hysteresis not defined\", \"Circadian regulation evidence is a single preprint lacking molecular dissection of IL-10Rα\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IL-10Rα proximal phosphotyrosine signaling is mechanistically coupled to both STAT3 and the AKT-mTOR branch, and what governs the switch-like control of receptor surface abundance across cell types, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the assembled ligand-bound receptor complex in the corpus\", \"Direct biochemical bridge from IL-10Rα to AKT-mTOR not established\", \"Unified mechanism linking receptor-expression state to functional output not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3, 5, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 12, 17]}\n    ],\n    \"complexes\": [\"IL-10 receptor\"],\n    \"partners\": [\"IL10\", \"JAK2\", \"STAT3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}