{"gene":"IL10RA","run_date":"2026-04-28T18:06:53","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 and activation of the downstream effector IL-10E1. Phosphorylated peptides encompassing these residues co-precipitate IL-10E1 and block ligand-dependent IL-10E1 phosphorylation, whereas peptides with serine substitutions at these positions do not prevent IL-10E1 activation.","method":"In vitro cell-free immunoprecipitation with phosphopeptides, site-directed mutagenesis (serine substitutions), confocal microscopy of GFP-fusion constructs, microinjection assays in human prostate cancer cell lines","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 — reconstitution in cell-free system, active-site mutagenesis, and in vivo confocal validation in single study with multiple orthogonal methods","pmids":["12802285"],"is_preprint":false},{"year":2012,"finding":"IFN-α priming upregulates IL-10R1 (IL-10RA) surface expression on human monocytes and macrophages, thereby increasing their sensitivity to IL-10 stimulation as measured by higher STAT3 phosphorylation, which in turn suppresses TLR-induced IL-12p70 production. IFN-β and IL-29 (type III IFN) produce a comparable effect, indicating a general IFN-class effect on IL-10RA-mediated signaling.","method":"Flow cytometry (IL-10R1 surface expression), Western blot (STAT3 phosphorylation), ELISA (IL-12p70), primary human monocyte/macrophage cultures with IFN priming","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — clean primary cell experiments with multiple readouts (surface receptor expression, downstream signaling, cytokine output) in a single lab","pmids":["22685028"],"is_preprint":false},{"year":2016,"finding":"BCL6 directly represses the IL10RA gene by binding to the JAK2 promoter and suppressing surface IL-10RA expression; BCL6 deficiency in Burkitt lymphoma cells elevates surface IL-10RA, increases JAK2 mRNA/protein, and activates STAT3 phosphorylation. Blockade of IL-10RA with an antibody represses STAT3 phosphorylation, defining an IL-10RA/JAK2/STAT3 survival pathway held in check by BCL6.","method":"Conditional BCL6-deficient cell line (DG75-AB7), synthetic lethal small-molecule screen, ChIP-seq (BCL6 binding at JAK2 promoter), in vitro ChIP, IL-10RA surface blockade with antibody, Western blot (STAT3 phosphorylation), xenograft in vivo studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP-seq for direct target validation, antibody blockade of IL-10RA with defined downstream STAT3 readout, in vitro and in vivo confirmation","pmids":["27268052"],"is_preprint":false},{"year":2016,"finding":"IL-10 inhibits starvation-induced autophagy in hypertrophic scar fibroblasts via IL-10Rα-mediated activation of both the STAT3 pathway and the AKT-mTOR pathway, converging at mTOR-p70S6K. Pharmacological blockade of IL-10Rα (using IL-10RB antagonist), p-AKT (LY294002), p-mTOR (rapamycin), or p-STAT3 (cryptotanshinone) each reversed IL-10-mediated autophagy inhibition.","method":"Transmission electron microscopy (autophagy), Western blot (p-AKT, p-STAT3, p-mTOR, p-p70S6K), pharmacological inhibitor dissection in primary hypertrophic scar fibroblasts, immunostaining and PCR for IL-10Rα expression","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal pharmacological inhibitors mapping pathway hierarchy, multiple mechanistic readouts in a single lab","pmids":["26962683"],"is_preprint":false},{"year":2016,"finding":"The synonymous IL10RA variant p.T179T, located before the 5' splice donor site of exon 4, causes exon skipping and out-of-frame fusion of exons 3 and 5, resulting in a non-functional receptor and defective STAT3 phosphorylation in response to IL-10 stimulation in patient PBMCs.","method":"Splicing analysis (RT-PCR demonstrating exon skipping), functional assay (STAT3 phosphorylation in patient-derived PBMCs stimulated with IL-10), Sanger sequencing","journal":"Journal of Crohn's & colitis","confidence":"Medium","confidence_rationale":"Tier 2 — direct splice-consequence demonstrated by RT-PCR plus downstream STAT3 functional readout in patient cells","pmids":["27177777"],"is_preprint":false},{"year":2016,"finding":"A novel exonic mutation in IL10RA (c.537G>A, p.T179T) causes unique splicing aberrations (exon skipping) resulting in loss of IL-10 receptor signaling, demonstrated by absent STAT3 phosphorylation in patient-derived cells stimulated with IL-10.","method":"Sanger sequencing, RT-PCR (splice aberration confirmation), functional IL-10 stimulation assay with STAT3 phosphorylation readout in patient PBMCs","journal":"BMC gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 — splicing consequence confirmed by RT-PCR and downstream signaling failure confirmed in patient-derived cells","pmids":["26822028"],"is_preprint":false},{"year":2019,"finding":"The IL-10RA missense variant p.Tyr91Cys causes structural instability by disrupting the hydrophobic core surrounding residue 91, resulting in failure of the mutant protein to properly localize to the plasma membrane and defective STAT3 activation in patient PBMCs upon IL-10 stimulation.","method":"Flow cytometry (plasma membrane localization of IL-10RA), confocal microscopy (GFP-fused mutant protein localization), STAT3 phosphorylation assay in patient PBMCs, computational structural analysis of IL-10RA protein","journal":"Inflammatory bowel diseases","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment tied to functional STAT3 signaling consequence, structural modeling provides mechanistic explanation","pmids":["30462267"],"is_preprint":false},{"year":2020,"finding":"Aberrant upregulation of IL-10RA in anaplastic large cell lymphoma (ALCL) cells rewires STAT3 signaling by providing an alternative route of STAT3 phosphorylation that bypasses dependence on NPM1-ALK, thereby driving resistance to the ALK inhibitor crizotinib. This was demonstrated by genome-wide CRISPR activation and knockout screens combined with RNA-seq from relapsed patient tumors.","method":"Genome-wide CRISPR activation screen, CRISPR knockout screen in ALCL cell lines, RNA-seq from ALK inhibitor-relapsed patient tumors, functional STAT3 signaling assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — genome-wide CRISPR screens with mechanistic follow-up (STAT3 pathway rewiring) validated in patient samples, multiple orthogonal approaches","pmids":["32573700"],"is_preprint":false},{"year":2021,"finding":"ATG16L1, via its C-terminal WD40 domain (WDD), interacts with IL10RB (the beta chain of the IL-10 receptor complex) after IL-10 activation to facilitate endocytosis, early trafficking, and downstream signaling of IL-10/IL-10R complexes, without influencing the degradation rate of the receptor complex.","method":"Binding motif identification, Co-immunoprecipitation (ATG16L1 WDD with IL10RB), endocytosis and trafficking assays, IL-10 signaling functional assays, WDD domain mutagenesis (indirect, via T300A allele analysis in follow-up paper)","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct interaction shown by pulldown/Co-IP, functional endocytosis/signaling consequence established, though primarily focused on IL10RB interaction rather than IL10RA directly","pmids":["34251955"],"is_preprint":false},{"year":2024,"finding":"In mesenchymal stem cells (MSCs), IL-10RA promotes IDO expression and T cell suppression through STAT3 phosphorylation. Knockdown of IL-10RA in MSCs significantly reduced IDO RNA and protein expression, decreased STAT3 phosphorylation, and inhibited IDO enzymatic activity, thereby relieving T cell suppression and restoring cytotoxicity against pancreatic cancer organoids.","method":"IL-10RA knockdown (siRNA/shRNA) in human bone marrow MSCs, co-culture with T cells, Western blot (IDO protein, p-STAT3), qRT-PCR (IDO RNA), IDO activity assay, PDAC organoid killing assay","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — knockdown with multiple mechanistic readouts (mRNA, protein, enzymatic activity, functional T cell killing) in a single lab","pmids":["39592739"],"is_preprint":false},{"year":2025,"finding":"The hysteretic nonlinearity of IL-10R expression drives tumor-infiltrated immune cells into a tumor-specific IL-10Rhi state. Bacteria (engineered Salmonella) exploit this state to enhance tumor-associated macrophage IL-10 production and evade neutrophil phagocytosis, while coincidentally expanding exhausted tumor-resident CD8+ T cells through the same IL-10R-driven mechanism.","method":"Engineered Salmonella strain in multiple tumor mouse models, flow cytometry of IL-10R expression states, functional assays (phagocytosis, T cell expansion, tumor regression), analysis of human tumor samples","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic demonstration across multiple tumor types with functional consequence readouts, though complexity of the bacterial system makes IL-10RA-specific dissection partial","pmids":["40037354"],"is_preprint":false},{"year":2006,"finding":"In SLE patient PBMCs, IL-10 stimulation through IL-10R activates JAK1, TYK2, STAT1, and STAT3 at levels comparable to healthy controls, indicating intact proximal signaling; however, the downstream gene expression pattern induced through IL-10R is aberrant in SLE, particularly in genes involved in apoptosis, cytokines, and their receptors.","method":"Flow cytometry (IL-10R expression), Western blot (JAK1, TYK2, STAT1, STAT3 phosphorylation), cDNA array (242 genes) after IL-10 stimulation of patient PBMCs","journal":"Scandinavian journal of rheumatology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single set of methods, descriptive downstream gene expression without mechanistic pathway placement","pmids":["17062437"],"is_preprint":false},{"year":2025,"finding":"IL-10RA promotes proliferation and fatty acid oxidation (FAO) in non-small cell lung cancer cells via the STAT3 signaling pathway. Overexpression of IL-10RA enhanced glycolysis and FAO while increasing STAT3 activation, and a STAT3 inhibitor blocked IL-10RA-driven FAO and proliferation.","method":"IL-10RA overexpression and knockdown in NSCLC cell lines, Seahorse metabolic assays (glycolysis, FAO), STAT3 inhibitor (pharmacological), Western blot, bioinformatic pathway analysis","journal":"Pulmonary pharmacology & therapeutics","confidence":"Low","confidence_rationale":"Tier 3 — single lab, pharmacological inhibitor without genetic rescue, no direct binding/interaction data","pmids":["39892560"],"is_preprint":false},{"year":2024,"finding":"The IL10RA enhancer SNP rs4936415 regulates IL10RA transcription: the protective G-allele shows higher enhancer activity in luciferase reporter assays, while the risk C-allele specifically binds NF-κB1 (shown by EMSA and ChIP), which also increases enhancer activity; BD patients with risk alleles show lower serum IL-10Rα levels.","method":"Luciferase gene-reporter assay, chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), ELISA (serum IL-10Rα), post-GWAS bioinformatic analysis","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 1–2 — multiple orthogonal mechanistic methods (EMSA, ChIP, reporter assay) in a single study establishing transcriptional regulatory mechanism","pmids":["39844988"],"is_preprint":false},{"year":2011,"finding":"Promoter SNPs in IL10RA (rs56356146 and rs7925112) alter IL10RA gene expression as demonstrated by transient transfection assays, and specific combined haplotypes of IL10RA and IL10RB promoter variants are associated with protection against severe malaria.","method":"Transient transfection assays for allele-specific reporter expression, population-based haplotype analysis in malaria cohorts","journal":"Immunogenetics","confidence":"Low","confidence_rationale":"Tier 3 — single lab, reporter assay for expression difference, no protein-level functional mechanistic follow-up","pmids":["21814839"],"is_preprint":false}],"current_model":"IL-10RA (IL-10 receptor alpha subunit) is a transmembrane receptor chain that, upon IL-10 binding, signals via specific cytoplasmic tyrosine residues (Tyr446 and Tyr496) to activate JAK1/TYK2 and downstream STAT3 phosphorylation; surface IL-10RA expression is upregulated by type I/III interferons to sensitize cells to IL-10, repressed transcriptionally by BCL6 to suppress an IL-10RA/JAK2/STAT3 survival pathway, regulated at the enhancer level by NF-κB1, and its endocytosis/early trafficking after IL-10 activation is facilitated by ATG16L1 WD40 domain interaction with IL-10RB; loss-of-function mutations that cause receptor mislocalization or splicing defects abolish STAT3 activation and underlie very early-onset inflammatory bowel disease, while aberrant IL-10RA upregulation in lymphoma drives alternative STAT3 phosphorylation enabling ALK inhibitor resistance."},"narrative":{"teleology":[{"year":2003,"claim":"Identification of the cytoplasmic signaling residues of IL-10RA resolved how the receptor couples ligand binding to downstream effector activation: Tyr446 and Tyr496 are necessary and sufficient for IL-10E1 recruitment and phosphorylation.","evidence":"Phosphopeptide co-precipitation, site-directed Tyr→Ser mutagenesis, and GFP-fusion confocal imaging in human cell lines","pmids":["12802285"],"confidence":"High","gaps":["Structural basis of selectivity between Tyr446 and Tyr496 for different STAT family members not resolved","No kinase reconstitution mapping which JAK isoform phosphorylates each tyrosine"]},{"year":2006,"claim":"Demonstration that proximal JAK1/TYK2–STAT1/STAT3 signaling downstream of IL-10RA is intact in SLE PBMCs established that disease-associated dysregulation occurs at the transcriptional output level rather than at receptor-proximal kinase activation.","evidence":"Phospho-Western blot for JAK1, TYK2, STAT1, STAT3 and cDNA array in SLE patient PBMCs","pmids":["17062437"],"confidence":"Low","gaps":["Single lab with descriptive gene-expression profiling; no mechanistic dissection of downstream transcriptional deviation","Small patient cohort limits generalizability"]},{"year":2012,"claim":"Type I and type III interferons were shown to upregulate surface IL-10RA on monocytes/macrophages, establishing a feed-forward mechanism by which antiviral interferons amplify IL-10 anti-inflammatory signaling through enhanced STAT3 phosphorylation.","evidence":"Flow cytometry for IL-10RA surface expression, phospho-STAT3 Western blot, and IL-12p70 ELISA in IFN-primed primary human monocytes/macrophages","pmids":["22685028"],"confidence":"Medium","gaps":["Transcription factor(s) mediating IFN-induced IL10RA upregulation not identified","Whether IFN-driven IL-10RA upregulation occurs in vivo during infection not tested"]},{"year":2016,"claim":"Three concurrent studies established that loss-of-function IL10RA mutations cause very-early-onset IBD through distinct molecular mechanisms—exon skipping from a synonymous variant (p.T179T) and protein misfolding/mislocalization from a missense variant (p.Tyr91Cys)—both converging on abolished STAT3 activation.","evidence":"RT-PCR for exon skipping, STAT3 phosphorylation assays in patient PBMCs, flow cytometry and confocal microscopy for membrane localization, structural modeling","pmids":["27177777","26822028","30462267"],"confidence":"Medium","gaps":["Rescue experiments (e.g., wild-type IL10RA transduction restoring STAT3 signaling) not reported for all variants","Whether these variants affect receptor complex formation with IL-10RB specifically not tested"]},{"year":2016,"claim":"BCL6 was identified as a direct transcriptional repressor of the IL-10RA/JAK2 axis, revealing that de-repression of IL-10RA surface expression activates a JAK2/STAT3 survival pathway in Burkitt lymphoma.","evidence":"ChIP-seq and in vitro ChIP for BCL6 binding at JAK2 promoter, conditional BCL6-deficient cell line, anti-IL-10RA antibody blockade abolishing STAT3 phosphorylation, xenograft validation","pmids":["27268052"],"confidence":"High","gaps":["Whether BCL6 binds the IL10RA promoter directly or acts solely through JAK2 regulation is not fully resolved","Generalizability to other B-cell lymphoma subtypes not established"]},{"year":2016,"claim":"IL-10RA was shown to inhibit autophagy through dual STAT3 and AKT-mTOR pathway activation, broadening IL-10RA signaling output beyond STAT3 alone.","evidence":"Pharmacological inhibitors of AKT, mTOR, and STAT3 each reversed IL-10-mediated autophagy suppression in primary hypertrophic scar fibroblasts; TEM for autophagosome quantification","pmids":["26962683"],"confidence":"Medium","gaps":["Whether AKT-mTOR activation occurs directly from IL-10RA cytoplasmic domain or indirectly via STAT3 target genes not distinguished","Genetic validation (e.g., IL-10RA knockdown) not performed"]},{"year":2020,"claim":"Genome-wide CRISPR screens revealed that aberrant IL-10RA upregulation provides a STAT3 phosphorylation bypass route in ALCL, explaining ALK inhibitor resistance and directly linking IL-10RA expression level to therapeutic outcome.","evidence":"CRISPR activation and knockout screens in ALCL cell lines, RNA-seq from ALK inhibitor-relapsed patient tumors, STAT3 signaling assays","pmids":["32573700"],"confidence":"High","gaps":["Therapeutic targeting of IL-10RA in resistant ALCL not yet tested","Whether IL-10RA upregulation is selected clonally or induced by the tumor microenvironment is unclear"]},{"year":2021,"claim":"ATG16L1 WD40 domain interaction with IL-10RB was shown to facilitate IL-10 receptor endocytosis and early trafficking, linking autophagy machinery to IL-10R signaling efficiency without affecting receptor degradation.","evidence":"Co-immunoprecipitation of ATG16L1 WDD with IL-10RB, endocytosis and trafficking assays after IL-10 stimulation","pmids":["34251955"],"confidence":"Medium","gaps":["Direct physical or functional role of ATG16L1 on IL-10RA (vs. IL-10RB) not demonstrated","Mechanism by which WDD facilitates endocytosis (adaptor recruitment, clathrin involvement) not resolved"]},{"year":2024,"claim":"IL-10RA signaling in mesenchymal stem cells was shown to drive IDO expression through STAT3, establishing a mechanism by which stromal cells suppress anti-tumor T cell responses in the pancreatic cancer microenvironment.","evidence":"IL-10RA knockdown in human bone marrow MSCs, co-culture with T cells, IDO activity assay, PDAC organoid killing assay","pmids":["39592739"],"confidence":"Medium","gaps":["Whether IL-10RA on MSCs is the dominant immunosuppressive receptor in vivo not established","Source of IL-10 in the tumor microenvironment driving this axis not identified"]},{"year":2024,"claim":"Enhancer-level regulation of IL10RA was mechanistically defined: the SNP rs4936415 C-allele recruits NF-κB1 to modulate enhancer activity and serum IL-10Rα levels, connecting genetic variation to receptor abundance.","evidence":"Luciferase reporter assay, EMSA and ChIP for NF-κB1 binding, ELISA for serum IL-10Rα in Behçet disease patients","pmids":["39844988"],"confidence":"Medium","gaps":["Whether NF-κB1-mediated regulation affects surface IL-10RA on immune cells specifically not tested","Functional consequence of altered serum IL-10Rα on IL-10 signaling not established"]},{"year":2025,"claim":"Nonlinear, hysteretic IL-10R expression dynamics were demonstrated in tumor-infiltrating immune cells, showing that the tumor microenvironment locks immune cells into an IL-10Rhi state exploitable by intratumoral bacteria.","evidence":"Engineered Salmonella in multiple mouse tumor models, flow cytometry of IL-10R states, phagocytosis and T cell expansion assays, human tumor sample analysis","pmids":["40037354"],"confidence":"Medium","gaps":["Molecular mechanism underlying hysteretic IL-10R expression (epigenetic, transcriptional feedback) not defined","IL-10RA vs. IL-10RB contribution to the hysteretic behavior not dissected"]},{"year":null,"claim":"The structural basis for how IL-10RA cytoplasmic domain differentially recruits JAK1 versus JAK2, and how receptor expression level quantitatively tunes the switch between immunosuppressive STAT3 signaling and oncogenic STAT3 bypass, remains mechanistically unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of full-length IL-10RA including the cytoplasmic domain","Quantitative threshold model for IL-10RA expression driving anti-inflammatory versus pro-tumoral STAT3 signaling not formalized","In vivo genetic rescue of IL10RA-deficient IBD models with defined mutants not reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,3,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,3,7,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,9,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5,6,7]}],"complexes":["IL-10 receptor complex (IL-10RA/IL-10RB)"],"partners":["IL10RB","JAK1","TYK2","STAT3","BCL6","JAK2","ATG16L1","NFKB1"],"other_free_text":[]},"mechanistic_narrative":"IL-10RA is the ligand-binding alpha chain of the interleukin-10 receptor that transduces anti-inflammatory and immunomodulatory signals through JAK1/TYK2-dependent STAT3 phosphorylation, with additional engagement of AKT-mTOR signaling in certain cell contexts. Two cytoplasmic tyrosine residues (Tyr446 and Tyr496) are essential for recruitment and activation of the downstream effector IL-10E1 and for productive STAT3 signaling [PMID:12802285], while surface IL-10RA abundance is dynamically regulated—upregulated by type I/III interferons to sensitize monocytes/macrophages to IL-10 [PMID:22685028], transcriptionally repressed by BCL6 to restrain an IL-10RA/JAK2/STAT3 survival circuit in B-cell lymphoma [PMID:27268052], and modulated at an enhancer by NF-κB1 binding [PMID:39844988]. Loss-of-function mutations—including missense variants that prevent plasma-membrane localization (p.Tyr91Cys) and synonymous variants that cause exon skipping (p.T179T)—abolish IL-10-induced STAT3 activation and underlie very-early-onset inflammatory bowel disease [PMID:30462267, PMID:27177777]. Conversely, aberrant IL-10RA upregulation in anaplastic large cell lymphoma provides a bypass route for STAT3 phosphorylation that confers resistance to ALK inhibitors [PMID:32573700]."},"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":193,"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":"22291593","id":"PMC_22291593","title":"IL-10R blockade during chronic schistosomiasis mansoni results in the loss of B cells from the liver and the development of severe pulmonary disease.","date":"2012","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/22291593","citation_count":53,"is_preprint":false},{"pmid":"40037354","id":"PMC_40037354","title":"Bacterial immunotherapy leveraging IL-10R hysteresis for both phagocytosis evasion and tumor immunity revitalization.","date":"2025","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/40037354","citation_count":48,"is_preprint":false},{"pmid":"17845543","id":"PMC_17845543","title":"Influence of IL-10RA and IL-22 polymorphisms on outcome of hepatitis C virus infection.","date":"2007","source":"Liver international : official journal of the International Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/17845543","citation_count":43,"is_preprint":false},{"pmid":"35481870","id":"PMC_35481870","title":"The clinical, molecular, and therapeutic features of patients with IL10/IL10R deficiency: a systematic review.","date":"2022","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35481870","citation_count":39,"is_preprint":false},{"pmid":"22685028","id":"PMC_22685028","title":"Type I and III interferons enhance IL-10R expression on human monocytes and macrophages, resulting in IL-10-mediated suppression of TLR-induced IL-12.","date":"2012","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22685028","citation_count":36,"is_preprint":false},{"pmid":"32573700","id":"PMC_32573700","title":"IL10RA modulates crizotinib sensitivity in NPM1-ALK+ anaplastic large cell lymphoma.","date":"2020","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/32573700","citation_count":35,"is_preprint":false},{"pmid":"26822028","id":"PMC_26822028","title":"Novel exonic mutation inducing aberrant splicing in the IL10RA gene and resulting in infantile-onset inflammatory bowel disease: a case report.","date":"2016","source":"BMC gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/26822028","citation_count":35,"is_preprint":false},{"pmid":"39215060","id":"PMC_39215060","title":"IL-10R inhibition reprograms tumor-associated macrophages and reverses drug resistance in multiple myeloma.","date":"2024","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/39215060","citation_count":33,"is_preprint":false},{"pmid":"25326368","id":"PMC_25326368","title":"Bone Marrow Mesenchymal Stromal Cells Induce Proliferative, Cytokinic and Molecular Changes During the T Cell Response: The Importance of the IL-10/CD210 Axis.","date":"2015","source":"Stem cell reviews and reports","url":"https://pubmed.ncbi.nlm.nih.gov/25326368","citation_count":33,"is_preprint":false},{"pmid":"34392305","id":"PMC_34392305","title":"Targeting of IL-10R on acute myeloid leukemia blasts with chimeric antigen receptor-expressing T cells.","date":"2021","source":"Blood cancer journal","url":"https://pubmed.ncbi.nlm.nih.gov/34392305","citation_count":31,"is_preprint":false},{"pmid":"27177777","id":"PMC_27177777","title":"A Synonymous Variant in IL10RA Affects RNA Splicing in Paediatric Patients with Refractory Inflammatory Bowel Disease.","date":"2016","source":"Journal of Crohn's & colitis","url":"https://pubmed.ncbi.nlm.nih.gov/27177777","citation_count":30,"is_preprint":false},{"pmid":"26481614","id":"PMC_26481614","title":"Association study of functional polymorphisms in interleukins and interleukin receptors genes: IL1A, IL1B, IL1RN, IL6, IL6R, IL10, IL10RA and TGFB1 in schizophrenia in Polish population.","date":"2015","source":"Schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/26481614","citation_count":29,"is_preprint":false},{"pmid":"29788474","id":"PMC_29788474","title":"Umbilical Cord Blood Transplantation Corrects Very Early-Onset Inflammatory Bowel Disease in Chinese Patients With IL10RA-Associated Immune Deficiency.","date":"2018","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/29788474","citation_count":29,"is_preprint":false},{"pmid":"23064239","id":"PMC_23064239","title":"Graphene oxide absorbed anti-IL10R antibodies enhance LPS induced immune responses in vitro and in vivo.","date":"2012","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/23064239","citation_count":28,"is_preprint":false},{"pmid":"27699073","id":"PMC_27699073","title":"Early Diagnosis and Hematopoietic Stem Cell Transplantation for IL10R Deficiency Leading to Very Early-Onset Inflammatory Bowel Disease Are Essential in Familial Cases.","date":"2016","source":"Case reports in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27699073","citation_count":21,"is_preprint":false},{"pmid":"20232770","id":"PMC_20232770","title":"Interleukin 10 receptor alpha subunit (IL-10RA) gene polymorphism and IL-10 serum levels in Egyptian atopic patients.","date":"2010","source":"Journal of investigational allergology & clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20232770","citation_count":21,"is_preprint":false},{"pmid":"28901380","id":"PMC_28901380","title":"Expression of CD19+CD24highCD38high B cells, IL‑10 and IL‑10R in peripheral blood from patients with systemic lupus erythematosus.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/28901380","citation_count":19,"is_preprint":false},{"pmid":"29730384","id":"PMC_29730384","title":"The expression of IL10RA in colorectal cancer and its correlation with the proliferation index and the clinical stage of the disease.","date":"2018","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/29730384","citation_count":19,"is_preprint":false},{"pmid":"23297791","id":"PMC_23297791","title":"Genetic evidence of regulatory gene variants of the STAT6, IL10R and FOXP3 locus as a susceptibility factor in uncomplicated malaria and parasitaemia in Congolese children.","date":"2013","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/23297791","citation_count":19,"is_preprint":false},{"pmid":"16160826","id":"PMC_16160826","title":"Polymorphism of the mouse gene for the interleukin 10 receptor alpha chain (Il10ra) and its association with the autoimmune phenotype.","date":"2005","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/16160826","citation_count":19,"is_preprint":false},{"pmid":"23455702","id":"PMC_23455702","title":"TLR4, IL10RA, and NOD2 mutation in paediatric Crohn's disease patients: an association with Mycobacterium avium subspecies paratuberculosis and TLR4 and IL10RA expression.","date":"2013","source":"Medical microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23455702","citation_count":18,"is_preprint":false},{"pmid":"32587451","id":"PMC_32587451","title":"Intestinal dysbiosis in pediatric Crohn's disease patients with IL10RA mutations.","date":"2020","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/32587451","citation_count":17,"is_preprint":false},{"pmid":"29755507","id":"PMC_29755507","title":"Computational Protein Phenotype Characterization of IL10RA Mutations Causative to Early Onset Inflammatory Bowel Disease (IBD).","date":"2018","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29755507","citation_count":14,"is_preprint":false},{"pmid":"27268052","id":"PMC_27268052","title":"Synthetic Lethal Screen Demonstrates That a JAK2 Inhibitor Suppresses a BCL6-dependent IL10RA/JAK2/STAT3 Pathway in High Grade B-cell Lymphoma.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27268052","citation_count":14,"is_preprint":false},{"pmid":"21814839","id":"PMC_21814839","title":"Combined promoter haplotypes of the IL10R genes are associated with protection against severe malaria in Gabonese children.","date":"2011","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/21814839","citation_count":14,"is_preprint":false},{"pmid":"31304220","id":"PMC_31304220","title":"Current concepts in pediatric inflammatory bowel disease; IL10/IL10R colitis as a model disease.","date":"2019","source":"International journal of pediatrics & adolescent medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31304220","citation_count":13,"is_preprint":false},{"pmid":"11566635","id":"PMC_11566635","title":"Semiautomated and simultaneous analysis of the interleukin-10 gene microsatellites IL-10G and IL-10R by fluorescence-based polymerase chain reaction reveals significant differences in allele distributions between Caucasians (Germany) and Africans (Gabon).","date":"2001","source":"European cytokine network","url":"https://pubmed.ncbi.nlm.nih.gov/11566635","citation_count":13,"is_preprint":false},{"pmid":"37033926","id":"PMC_37033926","title":"Combined therapy with methotrexate nanoconjugate and dendritic cells with downregulated IL-10R expression modulates the tumor microenvironment and enhances the systemic anti-tumor immune response in MC38 murine colon carcinoma.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37033926","citation_count":12,"is_preprint":false},{"pmid":"17062437","id":"PMC_17062437","title":"Expression and function of IL-10R in mononuclear cells from patients with systemic lupus erythematosus.","date":"2006","source":"Scandinavian journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/17062437","citation_count":11,"is_preprint":false},{"pmid":"30404730","id":"PMC_30404730","title":"A strategy of targeting B10 cell by CD19scFv-IL10R for tumor therapy.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30404730","citation_count":11,"is_preprint":false},{"pmid":"29724880","id":"PMC_29724880","title":"IL-10RA Mutation as a Risk Factor of Severe Influenza-Associated Encephalopathy: A Case Report.","date":"2018","source":"Pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/29724880","citation_count":11,"is_preprint":false},{"pmid":"39008193","id":"PMC_39008193","title":"A dual-targeting approach with anti-IL10R CAR-T cells engineered to release anti-CD33 bispecific antibody in enhancing killing effect on acute myeloid leukemia cells.","date":"2024","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/39008193","citation_count":10,"is_preprint":false},{"pmid":"10556270","id":"PMC_10556270","title":"Polymorphisms within the interleukin-10 receptor cDNA gene (IL10R) in Japanese patients with systemic lupus erythematosus.","date":"1999","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/10556270","citation_count":10,"is_preprint":false},{"pmid":"40535567","id":"PMC_40535567","title":"Mechanistic insights curcumin's anti-inflammatory in pancreatic cancer: experimental and computational evidence implicating IL1B interference via IL10RA upregulation and NLRP3/TLR3 downregulation.","date":"2025","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/40535567","citation_count":8,"is_preprint":false},{"pmid":"33316430","id":"PMC_33316430","title":"Association of variants in IL1B, TLR9, TREM1, IL10RA, and CD3G and Native American ancestry on malaria susceptibility in Colombian populations.","date":"2020","source":"Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/33316430","citation_count":8,"is_preprint":false},{"pmid":"37071310","id":"PMC_37071310","title":"Impact of Mycobacterium avium subsp. paratuberculosis infection on bovine IL10RA knockout mammary epithelial (MAC-T) cells.","date":"2023","source":"In vitro cellular & developmental biology. Animal","url":"https://pubmed.ncbi.nlm.nih.gov/37071310","citation_count":8,"is_preprint":false},{"pmid":"12802285","id":"PMC_12802285","title":"IL-10 signaling via IL-10E1 is dependent on tyrosine phosphorylation in the IL-10R alpha chain in human primary prostate cancer cell lines.","date":"2003","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12802285","citation_count":8,"is_preprint":false},{"pmid":"27796662","id":"PMC_27796662","title":"Genetic variant of IL-10RA and susceptibility to rheumatoid arthritis in a Chinese population.","date":"2016","source":"Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/27796662","citation_count":7,"is_preprint":false},{"pmid":"22649007","id":"PMC_22649007","title":"Genetic polymorphisms in IL10RA and TNF modify the association between blood transfusion and risk of non-Hodgkin lymphoma.","date":"2012","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/22649007","citation_count":6,"is_preprint":false},{"pmid":"33849446","id":"PMC_33849446","title":"Characterization of novel and large fragment deletions in exon 1 of the IL10RA gene in Chinese children with very early onset inflammatory bowel diseases.","date":"2021","source":"BMC gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/33849446","citation_count":6,"is_preprint":false},{"pmid":"29190678","id":"PMC_29190678","title":"Type I interferon signaling restrains IL-10R+ colonic macrophages and dendritic cells and leads to more severe Salmonella colitis.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29190678","citation_count":6,"is_preprint":false},{"pmid":"37511050","id":"PMC_37511050","title":"Association of IL10RA, IL10RB, and IL22RA Polymorphisms/Haplotypes with Susceptibility to and Clinical Manifestations of SLE.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37511050","citation_count":5,"is_preprint":false},{"pmid":"27397081","id":"PMC_27397081","title":"Family-based association study of interleukin 10 (IL10) and interleukin 10 receptor alpha (IL10RA) functional polymorphisms in schizophrenia in Polish population.","date":"2016","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/27397081","citation_count":5,"is_preprint":false},{"pmid":"30462267","id":"PMC_30462267","title":"Novel Compound Heterozygote Mutation in IL10RA in a Patient With Very Early-Onset Inflammatory Bowel Disease.","date":"2019","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/30462267","citation_count":5,"is_preprint":false},{"pmid":"29274771","id":"PMC_29274771","title":"Determination of normal expression patterns of CD86, CD210a, CD261, CD262, CD264, CD358, and CD361 in peripheral blood and bone marrow cells by flow cytometry.","date":"2017","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29274771","citation_count":5,"is_preprint":false},{"pmid":"30199474","id":"PMC_30199474","title":"Compound heterozygous mutations in IL10RA combined with a complement factor properdin mutation in infantile-onset inflammatory bowel disease.","date":"2018","source":"European journal of gastroenterology & hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/30199474","citation_count":5,"is_preprint":false},{"pmid":"34530396","id":"PMC_34530396","title":"Establishment of human induced pluripotent stem cell line (SDQLCHi040-A) from a patient with Infantile-onset inflammatory bowel disease carrying a homozygous mutation in IL10RA gene.","date":"2021","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/34530396","citation_count":5,"is_preprint":false},{"pmid":"39592739","id":"PMC_39592739","title":"IL-10RA governor the expression of IDO in the instruction of lymphocyte immunity.","date":"2024","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39592739","citation_count":4,"is_preprint":false},{"pmid":"34113591","id":"PMC_34113591","title":"Case Report: A Novel Compound Heterozygous Mutation in IL-10RA in a Chinese Child With Very Early-Onset Inflammatory Bowel Disease.","date":"2021","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/34113591","citation_count":4,"is_preprint":false},{"pmid":"31889944","id":"PMC_31889944","title":"Neonatal Crohn's disease with Oral ulcer as the first symptom caused by a compound heterozygote mutation in IL-10RA: a case report.","date":"2019","source":"Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/31889944","citation_count":4,"is_preprint":false},{"pmid":"39264505","id":"PMC_39264505","title":"Successful Allogeneic Hematopoietic Cell Transplantation for Patients with IL10RA Deficiency in Japan.","date":"2024","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39264505","citation_count":3,"is_preprint":false},{"pmid":"39950990","id":"PMC_39950990","title":"Successful Use of Anakinra in a Patient with IL-10R Beta Deficiency: A Case Report.","date":"2025","source":"Pediatric allergy, immunology, and pulmonology","url":"https://pubmed.ncbi.nlm.nih.gov/39950990","citation_count":3,"is_preprint":false},{"pmid":"40113867","id":"PMC_40113867","title":"Treatment of IL-10RA deficiency of pediatric patients with very early onset inflammatory bowel disease by allogeneic haematopoietic stem cell transplantation.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40113867","citation_count":3,"is_preprint":false},{"pmid":"31648101","id":"PMC_31648101","title":"An integration-free iPSC line (SDQLCHi012-A) derived from a patient with inflammatory bowel disease- 28 carrying compound heterozygote mutations in IL10RA gene.","date":"2019","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31648101","citation_count":3,"is_preprint":false},{"pmid":"33162889","id":"PMC_33162889","title":"Fecal Microbial Signatures Are Associated With Engraftment Failure Following Umbilical Cord Blood Transplantation in Pediatric Crohn's Disease Patients With IL10RA Deficiency.","date":"2020","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33162889","citation_count":3,"is_preprint":false},{"pmid":"34251955","id":"PMC_34251955","title":"Unconventional WD40 domain-dependent role of ATG16L1 in the regulation of IL10R (interleukin 10 receptor) endocytosis, trafficking and signaling.","date":"2021","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/34251955","citation_count":2,"is_preprint":false},{"pmid":"39892560","id":"PMC_39892560","title":"IL-10RA promotes lung cancer cell proliferation by increasing fatty acid oxidation via STAT3 signaling pathway.","date":"2025","source":"Pulmonary pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/39892560","citation_count":2,"is_preprint":false},{"pmid":"28349107","id":"PMC_28349107","title":"Data on IL-10R neutralization-induced chronic colitis in Lipocalin 2 deficient mice on BALB/c background.","date":"2017","source":"Data in brief","url":"https://pubmed.ncbi.nlm.nih.gov/28349107","citation_count":2,"is_preprint":false},{"pmid":"30498038","id":"PMC_30498038","title":"Association of IL-10 and IL-10RA single nucleotide polymorphisms with the responsiveness to HBV vaccination in Chinese infants of HBsAg(+)/HBeAg(-) mothers: a nested case-control study.","date":"2018","source":"BMJ open","url":"https://pubmed.ncbi.nlm.nih.gov/30498038","citation_count":2,"is_preprint":false},{"pmid":"40611267","id":"PMC_40611267","title":"Pitfalls in the diagnosis of apparent homozygous mutations: two cases of IL10RA deficiency inflammatory bowel disease and a literature review.","date":"2025","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/40611267","citation_count":1,"is_preprint":false},{"pmid":"25257438","id":"PMC_25257438","title":"Content of IL-10 and CD4+CD210+ cells in mice with adjuvant arthritis before and after treatment with cryopreserved placental cells.","date":"2014","source":"Bulletin of experimental biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25257438","citation_count":1,"is_preprint":false},{"pmid":"38495290","id":"PMC_38495290","title":"MiR-4763-3p accelerates lipopolysaccharide-induced cardiomyocyte apoptosis and inflammatory response by targeting IL10RA.","date":"2023","source":"Cytotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/38495290","citation_count":1,"is_preprint":false},{"pmid":"40654786","id":"PMC_40654786","title":"Lymphocytes and monocytes undergo swift suppression of IL-10R, IL-6R, and IL-2Rβγ signaling under high concentrations of different cytokines.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40654786","citation_count":1,"is_preprint":false},{"pmid":"30900524","id":"PMC_30900524","title":"Phenotypic characteristics and clinical manifestations of inflammatory bowel disease in infants and children under 2 years of age in Liaoning Province, China: five of six infants with IL-10R mutations.","date":"2019","source":"Paediatrics and international child health","url":"https://pubmed.ncbi.nlm.nih.gov/30900524","citation_count":1,"is_preprint":false},{"pmid":"36082572","id":"PMC_36082572","title":"[Clinical characteristics and identification of a novel IL10RA variant in association with very early-onset inflammatory bowel disease].","date":"2022","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36082572","citation_count":1,"is_preprint":false},{"pmid":"39687875","id":"PMC_39687875","title":"Characteristics of the gut microbiota and the effect of Bifidobacterium in very early-onset inflammatory bowel disease patients with IL10RA mutations.","date":"2024","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/39687875","citation_count":1,"is_preprint":false},{"pmid":"35311452","id":"PMC_35311452","title":"ATG16L1 WD40 domain-dependent IL10R (interleukin 10 receptor) signaling is insensitive to the T300A Crohn disease risk polymorphism.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/35311452","citation_count":0,"is_preprint":false},{"pmid":"39844988","id":"PMC_39844988","title":"Genetic predisposition to Behcet's disease mediated by a IL10RA enhancer polymorphism.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/39844988","citation_count":0,"is_preprint":false},{"pmid":"41606474","id":"PMC_41606474","title":"Exploring genotype-phenotype correlations in three pediatric patients with IL10RA variants and very early-onset inflammatory bowel disease.","date":"2026","source":"BMC gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/41606474","citation_count":0,"is_preprint":false},{"pmid":"41499552","id":"PMC_41499552","title":"IL-10R inhibition induces neutrophil tumoricidal activity.","date":"2026","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/41499552","citation_count":0,"is_preprint":false},{"pmid":"39506574","id":"PMC_39506574","title":"Correlation and Prediction of IL-10Ra and DKK-4 Plasma Levels in Patients with Calcium Oxalate Urolithiasis.","date":"2024","source":"Clinical laboratory","url":"https://pubmed.ncbi.nlm.nih.gov/39506574","citation_count":0,"is_preprint":false},{"pmid":"37906150","id":"PMC_37906150","title":"[Analysis of a child with Very early onset inflammatory bowel disease due to compound heterozygous variants of IL10RA and DUOX2 genes].","date":"2023","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37906150","citation_count":0,"is_preprint":false},{"pmid":"41846353","id":"PMC_41846353","title":"[Clinical Analysis of Allogeneic Hematopoietic Stem Cell Transplantation for Very Early-Onset Inflammatory Bowel Disease Caused by IL-10RA Mutation].","date":"2026","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/41846353","citation_count":0,"is_preprint":false},{"pmid":"41425514","id":"PMC_41425514","title":"Identification of Novel IL-10RA Variant in Infantile-Onset Inflammatory Bowel Disease: A Case Series With Preliminary Genotype-Phenotype Correlation From Two Chinese Families.","date":"2025","source":"Case reports in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41425514","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.07.680325","title":"Unveiling the temporal impact: Exploring dynamic changes in the paediatric solid tumour immune microenvironment through time","date":"2025-10-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.07.680325","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.11.659052","title":"A collection of patient-derived intestinal organoid lines reveals epithelial pheno-types associated with genetic drivers of pediatric inflammatory bowel disease","date":"2025-06-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.11.659052","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.03.641134","title":"Role of IL10 signaling in the circadian control of host response to Influenza infection","date":"2025-03-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.03.641134","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.05.07.592898","title":"Multiomic Screening Unravels the Immunometabolic Signatures and Drug Targets of Age-Related Macular Degeneration","date":"2024-05-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.05.07.592898","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.09.24315196","title":"Distinct proteomic signatures in Ethiopians predict acute and long-term sequelae of COVID-19","date":"2024-10-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.09.24315196","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45649,"output_tokens":4237,"usd":0.100251},"stage2":{"model":"claude-opus-4-6","input_tokens":7680,"output_tokens":3341,"usd":0.182888},"total_usd":0.283139,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Two specific tyrosine residues in the cytoplasmic domain of IL-10Rα (Tyr446 and Tyr496) are required for receptor function and for phosphorylation and activation of the downstream effector IL-10E1. Phosphorylated peptides encompassing these residues co-precipitate IL-10E1 and block ligand-dependent IL-10E1 phosphorylation, whereas peptides with serine substitutions at these positions do not prevent IL-10E1 activation.\",\n      \"method\": \"In vitro cell-free immunoprecipitation with phosphopeptides, site-directed mutagenesis (serine substitutions), confocal microscopy of GFP-fusion constructs, microinjection assays in human prostate cancer cell lines\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in cell-free system, active-site mutagenesis, and in vivo confocal validation in single study with multiple orthogonal methods\",\n      \"pmids\": [\"12802285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IFN-α priming upregulates IL-10R1 (IL-10RA) surface expression on human monocytes and macrophages, thereby increasing their sensitivity to IL-10 stimulation as measured by higher STAT3 phosphorylation, which in turn suppresses TLR-induced IL-12p70 production. IFN-β and IL-29 (type III IFN) produce a comparable effect, indicating a general IFN-class effect on IL-10RA-mediated signaling.\",\n      \"method\": \"Flow cytometry (IL-10R1 surface expression), Western blot (STAT3 phosphorylation), ELISA (IL-12p70), primary human monocyte/macrophage cultures with IFN priming\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean primary cell experiments with multiple readouts (surface receptor expression, downstream signaling, cytokine output) in a single lab\",\n      \"pmids\": [\"22685028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BCL6 directly represses the IL10RA gene by binding to the JAK2 promoter and suppressing surface IL-10RA expression; BCL6 deficiency in Burkitt lymphoma cells elevates surface IL-10RA, increases JAK2 mRNA/protein, and activates STAT3 phosphorylation. Blockade of IL-10RA with an antibody represses STAT3 phosphorylation, defining an IL-10RA/JAK2/STAT3 survival pathway held in check by BCL6.\",\n      \"method\": \"Conditional BCL6-deficient cell line (DG75-AB7), synthetic lethal small-molecule screen, ChIP-seq (BCL6 binding at JAK2 promoter), in vitro ChIP, IL-10RA surface blockade with antibody, Western blot (STAT3 phosphorylation), xenograft in vivo studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP-seq for direct target validation, antibody blockade of IL-10RA with defined downstream STAT3 readout, in vitro and in vivo confirmation\",\n      \"pmids\": [\"27268052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-10 inhibits starvation-induced autophagy in hypertrophic scar fibroblasts via IL-10Rα-mediated activation of both the STAT3 pathway and the AKT-mTOR pathway, converging at mTOR-p70S6K. Pharmacological blockade of IL-10Rα (using IL-10RB antagonist), p-AKT (LY294002), p-mTOR (rapamycin), or p-STAT3 (cryptotanshinone) each reversed IL-10-mediated autophagy inhibition.\",\n      \"method\": \"Transmission electron microscopy (autophagy), Western blot (p-AKT, p-STAT3, p-mTOR, p-p70S6K), pharmacological inhibitor dissection in primary hypertrophic scar fibroblasts, immunostaining and PCR for IL-10Rα expression\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal pharmacological inhibitors mapping pathway hierarchy, multiple mechanistic readouts in a single lab\",\n      \"pmids\": [\"26962683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The synonymous IL10RA variant p.T179T, located before the 5' splice donor site of exon 4, causes exon skipping and out-of-frame fusion of exons 3 and 5, resulting in a non-functional receptor and defective STAT3 phosphorylation in response to IL-10 stimulation in patient PBMCs.\",\n      \"method\": \"Splicing analysis (RT-PCR demonstrating exon skipping), functional assay (STAT3 phosphorylation in patient-derived PBMCs stimulated with IL-10), Sanger sequencing\",\n      \"journal\": \"Journal of Crohn's & colitis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct splice-consequence demonstrated by RT-PCR plus downstream STAT3 functional readout in patient cells\",\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 unique splicing aberrations (exon skipping) resulting in loss of IL-10 receptor signaling, demonstrated by absent STAT3 phosphorylation in patient-derived cells stimulated with IL-10.\",\n      \"method\": \"Sanger sequencing, RT-PCR (splice aberration confirmation), functional IL-10 stimulation assay with STAT3 phosphorylation readout in patient PBMCs\",\n      \"journal\": \"BMC gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — splicing consequence confirmed by RT-PCR and downstream signaling failure confirmed in patient-derived cells\",\n      \"pmids\": [\"26822028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The IL-10RA missense variant p.Tyr91Cys causes structural instability by disrupting the hydrophobic core surrounding residue 91, resulting in failure of the mutant protein to properly localize to the plasma membrane and defective STAT3 activation in patient PBMCs upon IL-10 stimulation.\",\n      \"method\": \"Flow cytometry (plasma membrane localization of IL-10RA), confocal microscopy (GFP-fused mutant protein localization), STAT3 phosphorylation assay in patient PBMCs, computational structural analysis of IL-10RA protein\",\n      \"journal\": \"Inflammatory bowel diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment tied to functional STAT3 signaling consequence, structural modeling provides mechanistic explanation\",\n      \"pmids\": [\"30462267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Aberrant upregulation of IL-10RA in anaplastic large cell lymphoma (ALCL) cells rewires STAT3 signaling by providing an alternative route of STAT3 phosphorylation that bypasses dependence on NPM1-ALK, thereby driving resistance to the ALK inhibitor crizotinib. This was demonstrated by genome-wide CRISPR activation and knockout screens combined with RNA-seq from relapsed patient tumors.\",\n      \"method\": \"Genome-wide CRISPR activation screen, CRISPR knockout screen in ALCL cell lines, RNA-seq from ALK inhibitor-relapsed patient tumors, functional STAT3 signaling assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genome-wide CRISPR screens with mechanistic follow-up (STAT3 pathway rewiring) validated in patient samples, multiple orthogonal approaches\",\n      \"pmids\": [\"32573700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATG16L1, via its C-terminal WD40 domain (WDD), interacts with IL10RB (the beta chain of the IL-10 receptor complex) after IL-10 activation to facilitate endocytosis, early trafficking, and downstream signaling of IL-10/IL-10R complexes, without influencing the degradation rate of the receptor complex.\",\n      \"method\": \"Binding motif identification, Co-immunoprecipitation (ATG16L1 WDD with IL10RB), endocytosis and trafficking assays, IL-10 signaling functional assays, WDD domain mutagenesis (indirect, via T300A allele analysis in follow-up paper)\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct interaction shown by pulldown/Co-IP, functional endocytosis/signaling consequence established, though primarily focused on IL10RB interaction rather than IL10RA directly\",\n      \"pmids\": [\"34251955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In mesenchymal stem cells (MSCs), IL-10RA promotes IDO expression and T cell suppression through STAT3 phosphorylation. Knockdown of IL-10RA in MSCs significantly reduced IDO RNA and protein expression, decreased STAT3 phosphorylation, and inhibited IDO enzymatic activity, thereby relieving T cell suppression and restoring cytotoxicity against pancreatic cancer organoids.\",\n      \"method\": \"IL-10RA knockdown (siRNA/shRNA) in human bone marrow MSCs, co-culture with T cells, Western blot (IDO protein, p-STAT3), qRT-PCR (IDO RNA), IDO activity assay, PDAC organoid killing assay\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — knockdown with multiple mechanistic readouts (mRNA, protein, enzymatic activity, functional T cell killing) in a single lab\",\n      \"pmids\": [\"39592739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The hysteretic nonlinearity of IL-10R expression drives tumor-infiltrated immune cells into a tumor-specific IL-10Rhi state. Bacteria (engineered Salmonella) exploit this state to enhance tumor-associated macrophage IL-10 production and evade neutrophil phagocytosis, while coincidentally expanding exhausted tumor-resident CD8+ T cells through the same IL-10R-driven mechanism.\",\n      \"method\": \"Engineered Salmonella strain in multiple tumor mouse models, flow cytometry of IL-10R expression states, functional assays (phagocytosis, T cell expansion, tumor regression), analysis of human tumor samples\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic demonstration across multiple tumor types with functional consequence readouts, though complexity of the bacterial system makes IL-10RA-specific dissection partial\",\n      \"pmids\": [\"40037354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In SLE patient PBMCs, IL-10 stimulation through IL-10R activates JAK1, TYK2, STAT1, and STAT3 at levels comparable to healthy controls, indicating intact proximal signaling; however, the downstream gene expression pattern induced through IL-10R is aberrant in SLE, particularly in genes involved in apoptosis, cytokines, and their receptors.\",\n      \"method\": \"Flow cytometry (IL-10R expression), Western blot (JAK1, TYK2, STAT1, STAT3 phosphorylation), cDNA array (242 genes) after IL-10 stimulation of patient PBMCs\",\n      \"journal\": \"Scandinavian journal of rheumatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single set of methods, descriptive downstream gene expression without mechanistic pathway placement\",\n      \"pmids\": [\"17062437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-10RA promotes proliferation and fatty acid oxidation (FAO) in non-small cell lung cancer cells via the STAT3 signaling pathway. Overexpression of IL-10RA enhanced glycolysis and FAO while increasing STAT3 activation, and a STAT3 inhibitor blocked IL-10RA-driven FAO and proliferation.\",\n      \"method\": \"IL-10RA overexpression and knockdown in NSCLC cell lines, Seahorse metabolic assays (glycolysis, FAO), STAT3 inhibitor (pharmacological), Western blot, bioinformatic pathway analysis\",\n      \"journal\": \"Pulmonary pharmacology & therapeutics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, pharmacological inhibitor without genetic rescue, no direct binding/interaction data\",\n      \"pmids\": [\"39892560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The IL10RA enhancer SNP rs4936415 regulates IL10RA transcription: the protective G-allele shows higher enhancer activity in luciferase reporter assays, while the risk C-allele specifically binds NF-κB1 (shown by EMSA and ChIP), which also increases enhancer activity; BD patients with risk alleles show lower serum IL-10Rα levels.\",\n      \"method\": \"Luciferase gene-reporter assay, chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), ELISA (serum IL-10Rα), post-GWAS bioinformatic analysis\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal mechanistic methods (EMSA, ChIP, reporter assay) in a single study establishing transcriptional regulatory mechanism\",\n      \"pmids\": [\"39844988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Promoter SNPs in IL10RA (rs56356146 and rs7925112) alter IL10RA gene expression as demonstrated by transient transfection assays, and specific combined haplotypes of IL10RA and IL10RB promoter variants are associated with protection against severe malaria.\",\n      \"method\": \"Transient transfection assays for allele-specific reporter expression, population-based haplotype analysis in malaria cohorts\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, reporter assay for expression difference, no protein-level functional mechanistic follow-up\",\n      \"pmids\": [\"21814839\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-10RA (IL-10 receptor alpha subunit) is a transmembrane receptor chain that, upon IL-10 binding, signals via specific cytoplasmic tyrosine residues (Tyr446 and Tyr496) to activate JAK1/TYK2 and downstream STAT3 phosphorylation; surface IL-10RA expression is upregulated by type I/III interferons to sensitize cells to IL-10, repressed transcriptionally by BCL6 to suppress an IL-10RA/JAK2/STAT3 survival pathway, regulated at the enhancer level by NF-κB1, and its endocytosis/early trafficking after IL-10 activation is facilitated by ATG16L1 WD40 domain interaction with IL-10RB; loss-of-function mutations that cause receptor mislocalization or splicing defects abolish STAT3 activation and underlie very early-onset inflammatory bowel disease, while aberrant IL-10RA upregulation in lymphoma drives alternative STAT3 phosphorylation enabling ALK inhibitor resistance.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL-10RA is the ligand-binding alpha chain of the interleukin-10 receptor that transduces anti-inflammatory and immunomodulatory signals through JAK1/TYK2-dependent STAT3 phosphorylation, with additional engagement of AKT-mTOR signaling in certain cell contexts. Two cytoplasmic tyrosine residues (Tyr446 and Tyr496) are essential for recruitment and activation of the downstream effector IL-10E1 and for productive STAT3 signaling [PMID:12802285], while surface IL-10RA abundance is dynamically regulated—upregulated by type I/III interferons to sensitize monocytes/macrophages to IL-10 [PMID:22685028], transcriptionally repressed by BCL6 to restrain an IL-10RA/JAK2/STAT3 survival circuit in B-cell lymphoma [PMID:27268052], and modulated at an enhancer by NF-κB1 binding [PMID:39844988]. Loss-of-function mutations—including missense variants that prevent plasma-membrane localization (p.Tyr91Cys) and synonymous variants that cause exon skipping (p.T179T)—abolish IL-10-induced STAT3 activation and underlie very-early-onset inflammatory bowel disease [PMID:30462267, PMID:27177777]. Conversely, aberrant IL-10RA upregulation in anaplastic large cell lymphoma provides a bypass route for STAT3 phosphorylation that confers resistance to ALK inhibitors [PMID:32573700].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of the cytoplasmic signaling residues of IL-10RA resolved how the receptor couples ligand binding to downstream effector activation: Tyr446 and Tyr496 are necessary and sufficient for IL-10E1 recruitment and phosphorylation.\",\n      \"evidence\": \"Phosphopeptide co-precipitation, site-directed Tyr→Ser mutagenesis, and GFP-fusion confocal imaging in human cell lines\",\n      \"pmids\": [\"12802285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of selectivity between Tyr446 and Tyr496 for different STAT family members not resolved\",\n        \"No kinase reconstitution mapping which JAK isoform phosphorylates each tyrosine\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstration that proximal JAK1/TYK2–STAT1/STAT3 signaling downstream of IL-10RA is intact in SLE PBMCs established that disease-associated dysregulation occurs at the transcriptional output level rather than at receptor-proximal kinase activation.\",\n      \"evidence\": \"Phospho-Western blot for JAK1, TYK2, STAT1, STAT3 and cDNA array in SLE patient PBMCs\",\n      \"pmids\": [\"17062437\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single lab with descriptive gene-expression profiling; no mechanistic dissection of downstream transcriptional deviation\",\n        \"Small patient cohort limits generalizability\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Type I and type III interferons were shown to upregulate surface IL-10RA on monocytes/macrophages, establishing a feed-forward mechanism by which antiviral interferons amplify IL-10 anti-inflammatory signaling through enhanced STAT3 phosphorylation.\",\n      \"evidence\": \"Flow cytometry for IL-10RA surface expression, phospho-STAT3 Western blot, and IL-12p70 ELISA in IFN-primed primary human monocytes/macrophages\",\n      \"pmids\": [\"22685028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Transcription factor(s) mediating IFN-induced IL10RA upregulation not identified\",\n        \"Whether IFN-driven IL-10RA upregulation occurs in vivo during infection not tested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Three concurrent studies established that loss-of-function IL10RA mutations cause very-early-onset IBD through distinct molecular mechanisms—exon skipping from a synonymous variant (p.T179T) and protein misfolding/mislocalization from a missense variant (p.Tyr91Cys)—both converging on abolished STAT3 activation.\",\n      \"evidence\": \"RT-PCR for exon skipping, STAT3 phosphorylation assays in patient PBMCs, flow cytometry and confocal microscopy for membrane localization, structural modeling\",\n      \"pmids\": [\"27177777\", \"26822028\", \"30462267\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Rescue experiments (e.g., wild-type IL10RA transduction restoring STAT3 signaling) not reported for all variants\",\n        \"Whether these variants affect receptor complex formation with IL-10RB specifically not tested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"BCL6 was identified as a direct transcriptional repressor of the IL-10RA/JAK2 axis, revealing that de-repression of IL-10RA surface expression activates a JAK2/STAT3 survival pathway in Burkitt lymphoma.\",\n      \"evidence\": \"ChIP-seq and in vitro ChIP for BCL6 binding at JAK2 promoter, conditional BCL6-deficient cell line, anti-IL-10RA antibody blockade abolishing STAT3 phosphorylation, xenograft validation\",\n      \"pmids\": [\"27268052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether BCL6 binds the IL10RA promoter directly or acts solely through JAK2 regulation is not fully resolved\",\n        \"Generalizability to other B-cell lymphoma subtypes not established\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"IL-10RA was shown to inhibit autophagy through dual STAT3 and AKT-mTOR pathway activation, broadening IL-10RA signaling output beyond STAT3 alone.\",\n      \"evidence\": \"Pharmacological inhibitors of AKT, mTOR, and STAT3 each reversed IL-10-mediated autophagy suppression in primary hypertrophic scar fibroblasts; TEM for autophagosome quantification\",\n      \"pmids\": [\"26962683\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether AKT-mTOR activation occurs directly from IL-10RA cytoplasmic domain or indirectly via STAT3 target genes not distinguished\",\n        \"Genetic validation (e.g., IL-10RA knockdown) not performed\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genome-wide CRISPR screens revealed that aberrant IL-10RA upregulation provides a STAT3 phosphorylation bypass route in ALCL, explaining ALK inhibitor resistance and directly linking IL-10RA expression level to therapeutic outcome.\",\n      \"evidence\": \"CRISPR activation and knockout screens in ALCL cell lines, RNA-seq from ALK inhibitor-relapsed patient tumors, STAT3 signaling assays\",\n      \"pmids\": [\"32573700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Therapeutic targeting of IL-10RA in resistant ALCL not yet tested\",\n        \"Whether IL-10RA upregulation is selected clonally or induced by the tumor microenvironment is unclear\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ATG16L1 WD40 domain interaction with IL-10RB was shown to facilitate IL-10 receptor endocytosis and early trafficking, linking autophagy machinery to IL-10R signaling efficiency without affecting receptor degradation.\",\n      \"evidence\": \"Co-immunoprecipitation of ATG16L1 WDD with IL-10RB, endocytosis and trafficking assays after IL-10 stimulation\",\n      \"pmids\": [\"34251955\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical or functional role of ATG16L1 on IL-10RA (vs. IL-10RB) not demonstrated\",\n        \"Mechanism by which WDD facilitates endocytosis (adaptor recruitment, clathrin involvement) not resolved\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"IL-10RA signaling in mesenchymal stem cells was shown to drive IDO expression through STAT3, establishing a mechanism by which stromal cells suppress anti-tumor T cell responses in the pancreatic cancer microenvironment.\",\n      \"evidence\": \"IL-10RA knockdown in human bone marrow MSCs, co-culture with T cells, IDO activity assay, PDAC organoid killing assay\",\n      \"pmids\": [\"39592739\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether IL-10RA on MSCs is the dominant immunosuppressive receptor in vivo not established\",\n        \"Source of IL-10 in the tumor microenvironment driving this axis not identified\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Enhancer-level regulation of IL10RA was mechanistically defined: the SNP rs4936415 C-allele recruits NF-κB1 to modulate enhancer activity and serum IL-10Rα levels, connecting genetic variation to receptor abundance.\",\n      \"evidence\": \"Luciferase reporter assay, EMSA and ChIP for NF-κB1 binding, ELISA for serum IL-10Rα in Behçet disease patients\",\n      \"pmids\": [\"39844988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether NF-κB1-mediated regulation affects surface IL-10RA on immune cells specifically not tested\",\n        \"Functional consequence of altered serum IL-10Rα on IL-10 signaling not established\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Nonlinear, hysteretic IL-10R expression dynamics were demonstrated in tumor-infiltrating immune cells, showing that the tumor microenvironment locks immune cells into an IL-10Rhi state exploitable by intratumoral bacteria.\",\n      \"evidence\": \"Engineered Salmonella in multiple mouse tumor models, flow cytometry of IL-10R states, phagocytosis and T cell expansion assays, human tumor sample analysis\",\n      \"pmids\": [\"40037354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism underlying hysteretic IL-10R expression (epigenetic, transcriptional feedback) not defined\",\n        \"IL-10RA vs. IL-10RB contribution to the hysteretic behavior not dissected\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for how IL-10RA cytoplasmic domain differentially recruits JAK1 versus JAK2, and how receptor expression level quantitatively tunes the switch between immunosuppressive STAT3 signaling and oncogenic STAT3 bypass, remains mechanistically unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of full-length IL-10RA including the cytoplasmic domain\",\n        \"Quantitative threshold model for IL-10RA expression driving anti-inflammatory versus pro-tumoral STAT3 signaling not formalized\",\n        \"In vivo genetic rescue of IL10RA-deficient IBD models with defined mutants not reported\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 3, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 3, 7, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 9, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5, 6, 7]}\n    ],\n    \"complexes\": [\n      \"IL-10 receptor complex (IL-10RA/IL-10RB)\"\n    ],\n    \"partners\": [\n      \"IL10RB\",\n      \"JAK1\",\n      \"TYK2\",\n      \"STAT3\",\n      \"BCL6\",\n      \"JAK2\",\n      \"ATG16L1\",\n      \"NFKB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}