{"gene":"IL1RN","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1992,"finding":"IL1RN gene maps to chromosome 2q14-q21, in the same region as IL-1alpha and IL-1beta loci, consistent with an early gene duplication event creating an interleukin-1 gene family.","method":"Somatic rodent-human cell hybrid panel analysis and linkage analysis in CEPH families using a length variation polymorphism in intron 2","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chromosomal mapping by cell hybrid panel and family linkage, two orthogonal approaches in one study","pmids":["1386337"],"is_preprint":false},{"year":1993,"finding":"The human IL1RN gene was localized to chromosome 2q14.2 by fluorescence in situ hybridization using a yeast artificial chromosome containing IL1RN as a probe, near the IL-1alpha, IL-1beta, and IL-1 receptor genes.","method":"FISH with YAC probe; Southern blot of human-Chinese hamster cell hybrids","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal localization methods (FISH + Southern blot of hybrid cells), single study","pmids":["8432529"],"is_preprint":false},{"year":2009,"finding":"Homozygous deletion of the IL1RN locus (175-kb deletion at chromosome 2q13) causes a severe autoinflammatory disease (DIRA) characterized by pustular rash, lytic bone lesions, osteopenia, respiratory insufficiency, and thrombosis; mononuclear cells from the patient produced markedly elevated inflammatory cytokines, and treatment with anakinra (recombinant IL-1Ra) completely resolved symptoms, establishing that absence of IL-1Ra protein causes unchecked IL-1 signaling.","method":"Genetic analysis (homozygous deletion identified), ex vivo cytokine production assay of patient mononuclear cells, therapeutic rescue with anakinra","journal":"The New England journal of medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — human loss-of-function genetic variant with defined cellular phenotype (excess cytokine production) and therapeutic rescue, replicated across multiple DIRA reports","pmids":["19494219"],"is_preprint":false},{"year":2011,"finding":"A novel homozygous 15-bp in-frame deletion in IL1RN produces a mutant IL-1Ra protein that has no affinity for the IL-1 receptor in vitro, and patient cells stimulated with IL-1alpha or IL-1beta showed oversecretion of proinflammatory cytokines, demonstrating that receptor binding is required for IL-1Ra's anti-inflammatory function.","method":"In vitro expression of mutant protein with IL-1 receptor binding assay; stimulation of patient cells with recombinant IL-1alpha/IL-1beta and cytokine measurement","journal":"Arthritis and rheumatism","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro receptor binding assay with mutant protein plus functional cell assay in patient-derived cells, single lab with two orthogonal methods","pmids":["22127713"],"is_preprint":false},{"year":2010,"finding":"In Il1rn-/- mice, spontaneous psoriasis-like dermatitis is driven by excess IL-1 signaling that directly activates keratinocytes to produce TNF and chemokines; development of dermatitis requires TNF (completely suppressed in Tnfsf1a-/- mice) but not IL-6 or IL-17, and is T-cell independent (lesions develop in Il1rn-/- SCID mice; adoptive transfer of Il1rn-/- T cells does not induce dermatitis). Bone marrow transplantation showed that TNF from skin-resident (non-bone marrow-derived) cells is critical.","method":"Genetic knockout mice (Il1rn-/-, Tnfsf1a-/-, Il6-/-, IL-17-deficient crosses); adoptive transfer experiments into SCID mice; bone marrow transplantation; cytokine/chemokine measurement at inflammation site","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic approaches (KO crosses, adoptive transfer, BMT), defining both the pathway (IL-1 → keratinocyte TNF) and the cell type responsible","pmids":["20610641"],"is_preprint":false},{"year":2012,"finding":"In Il1rn-/- mice exposed to aerosolized LPS, resolution of lung inflammation is delayed relative to wild-type, with increased BAL neutrophils, elevated IL-17A expression (from gamma-delta T cells), and elevated G-CSF. Blockade of IL-17A reduced BAL neutrophil counts and lung G-CSF expression in Il1rn-/- mice, placing IL-1Ra upstream of the IL-17A/G-CSF axis in resolution of acute lung inflammation.","method":"Knockout mouse model (Il1rn-/-) with aerosolized LPS; BAL cell counts and protein measurement; cytokine/RNA profiling; IL-17A monoclonal antibody blockade","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype, pathway placed by antibody blockade, two orthogonal intervention methods","pmids":["22592923"],"is_preprint":false},{"year":2011,"finding":"The IL1RN promoter SNP rs4251961 (C allele) is associated with increased plasma IL-1Ra concentrations during invasive pneumococcal disease. Functional reporter assays in HEK293T cells showed that the C allele promoter construct has ~9-fold increased activity versus ~6-fold for the T allele in the presence of GATA-1, identifying GATA-1 as a differential transcriptional regulator of IL1RN expression at this locus.","method":"Promoter-reporter (luciferase) transfection assay in HEK293T cells with and without GATA-1 overexpression; plasma IL-1Ra measurement in 299 children with invasive pneumococcal disease; validation in HIV-infected adult cohort","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter assay with transcription factor co-transfection plus in vivo correlation in two independent cohorts, single lab","pmids":["21248262"],"is_preprint":false},{"year":2013,"finding":"The IL1RN coding variant rs315952C is associated with decreased risk of ARDS in three independent populations; carriers of rs315952C have higher plasma IL-1Ra levels, establishing that this synonymous variant functionally influences IL1Ra protein levels and thereby modulates ARDS susceptibility.","method":"Multi-stage genetic association study (three critically ill cohorts, n=3065 total); ELISA for plasma IL-1Ra protein levels stratified by genotype","journal":"American journal of respiratory and critical care medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated in three independent populations with paired protein level measurement, demonstrating functional consequence of the variant","pmids":["23449693"],"is_preprint":false},{"year":2014,"finding":"The IL1RN synonymous coding variant rs315952C is preferentially transcribed (allelic imbalance demonstrated by RNA sequencing of adipose tissue), leading to higher evoked plasma IL-1Ra after LPS challenge and improved survival in septic shock, establishing that this variant acts at the level of mRNA expression to modulate IL-1Ra protein levels and downstream clinical outcomes.","method":"RNA sequencing of adipose tissue for allelic imbalance; human LPS endotoxin challenge model (n=294 volunteers) with plasma IL-1Ra ELISA; genetic association study for survival in the VASST septic shock cohort","journal":"American journal of respiratory and critical care medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — allelic imbalance by RNA-seq provides mechanistic basis; validated in controlled human LPS model and independent septic shock cohort","pmids":["25089931"],"is_preprint":false},{"year":2012,"finding":"The IL1RN VNTR*2 haploblock is associated with IPF susceptibility, and the IL1RN SNP rs2637988 significantly influences IL-1Ra mRNA expression levels (carriers of the minor GG genotype have lower mRNA), suggesting that reduced IL-1Ra expression predisposes to pulmonary fibrosis.","method":"Meta-analysis of five case-control studies; IL1RN mRNA expression analysis correlated with genotype in patient samples","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mRNA expression-genotype correlation in patient samples with meta-analysis replication, but no direct functional manipulation","pmids":["22322675"],"is_preprint":false},{"year":2021,"finding":"Intracellular IL-1RA type 1 (icIL-1RA1, a product of IL1RN) is progressively lost during oral carcinogenesis; CRISPR/Cas9-mediated knockdown of icIL-1RA1 in normal and dysplastic oral keratinocytes caused increased IL-6 and IL-8 secretion and accelerated senescence, establishing icIL-1RA1 as a regulator of the senescence-associated secretory phenotype (SASP).","method":"CRISPR/Cas9 knockdown in primary keratinocytes; IL-6/IL-8 ELISA; senescence assay; ex vivo tissue expression analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR loss-of-function with defined cytokine phenotype, single lab","pmids":["33526711"],"is_preprint":false},{"year":2021,"finding":"IL1RN promotes osteoblast differentiation by interacting with integrin beta3 (ITGB3) to activate beta-catenin signaling; silencing IL1RN attenuated osteogenic differentiation while overexpression increased alkaline phosphatase, osterix, and osteocalcin expression in MC3T3-E1 and C3H10T1/2 cells.","method":"IL1RN knockdown and overexpression in osteoblast cell lines; co-interaction assay with ITGB3; osteogenic staining; Western blot for osteogenic markers and beta-catenin pathway components","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — gain- and loss-of-function with pathway readout, interaction with ITGB3 identified, single lab","pmids":["33493267"],"is_preprint":false},{"year":2019,"finding":"IL1RN mediates the suppressive effect of methionine deprivation on glioma cell proliferation; methionine deprivation or IL1RN knockdown induced glioma cell cycle arrest both in vitro and in vivo.","method":"Methionine deprivation experiments in glioma cell lines; IL1RN knockdown; cell cycle analysis; in vivo tumor model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal interventions (metabolic deprivation + gene knockdown) with defined cell cycle phenotype, single lab","pmids":["30978442"],"is_preprint":false},{"year":2023,"finding":"In KRAS-mutant intrahepatic cholangiocarcinoma, alternative splicing upregulates IL1RN-201/203 isoforms as a negative feedback mechanism; both IL1RN-201/203 upregulation and anakinra treatment altered neutrophil recruitment/phenotypes and activated intratumoral GZMB+ CD8+ T cells, and synergized with anti-PD-1 therapy in KRAS-mutant iCCA mouse models.","method":"Multiomics analysis of patient samples; in vivo KRAS-mutant iCCA mouse models with IL1RN isoform overexpression and anakinra treatment; flow cytometry for immune cell phenotyping; combination with anti-PD-1","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model with genetic and pharmacologic interventions, immune phenotyping, single study","pmids":["37486241"],"is_preprint":false},{"year":2024,"finding":"Exosomal miR-125a-5p from cigarette smoke-exposed bronchial epithelial cells is taken up by macrophages and targets IL1RN (confirmed by luciferase reporter assay), reducing IL-1Ra expression and promoting M1 macrophage polarization via the MyD88/NF-κB pathway.","method":"Luciferase reporter assay for miR-125a-5p targeting of IL1RN 3'UTR; PKH26-labeled exosome uptake; co-culture of epithelial cells and macrophages; miR-125a-5p mimic/inhibitor transfection; in vivo COPD mouse model with miR-125a-5p inhibitor","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation by luciferase assay plus in vivo rescue, single lab","pmids":["38875998"],"is_preprint":false},{"year":2021,"finding":"miR-122-5p directly targets IL1RN (confirmed by TargetScan prediction and dual luciferase reporter assay); miR-122-5p mimics decreased cell viability and promoted apoptosis/inflammation in LPS-treated A549 cells, and these effects were reversed by IL1RN siRNA knockdown, establishing IL1RN as a functional target of miR-122-5p in LPS-induced lung injury.","method":"Dual luciferase reporter gene assay; miR-122-5p mimic/inhibitor transfection; IL1RN siRNA; LPS-induced ALI cell model; ELISA for TNF-alpha, IL-1beta, IL-6","journal":"Experimental and therapeutic medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase assay for direct targeting plus epistasis rescue experiment, single lab","pmids":["34594415"],"is_preprint":false},{"year":2023,"finding":"The transcription factor ELF4 activates IL1RN transcription; dual-luciferase and ChIP assays in BMDMs and intestinal epithelial cells demonstrated ELF4 binding to the IL1RN promoter and increased IL1RN promoter activity. ELF4-driven IL1RN upregulation suppressed inflammatory TH17 cell activity and induced macrophage M2 polarization to alleviate experimental colitis.","method":"Dual-luciferase reporter assay; ChIP assay; ELF4 overexpression in vivo (LPS-induced colitis mouse model); flow cytometry for macrophage polarization and TH17 cells; ELISA","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase assays establish direct ELF4-IL1RN promoter interaction, functional in vivo rescue, single lab","pmids":["38022496"],"is_preprint":false},{"year":2003,"finding":"The IL-1RN*2/*2 genotype is associated with decreased endothelial cell (EC) cumulative population doublings and reduced proliferation at later passage, with increased senescent ECs. Addition of exogenous IL-1Ra (1 ng/mL) increased proliferation of IL-1RN*2/*2 ECs, suggesting that IL-1Ra promotes EC replicative capacity.","method":"Ex vivo EC culture from human donors stratified by IL-1RN genotype; Ki67 proliferation assay; cumulative population doubling counts; exogenous IL-1Ra supplementation","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genotype-stratified functional assay with pharmacological rescue, single lab with multiple readouts","pmids":["12764021"],"is_preprint":false}],"current_model":"IL1RN encodes interleukin-1 receptor antagonist (IL-1Ra), a secreted and intracellular protein that competitively inhibits IL-1alpha and IL-1beta binding to the IL-1 receptor; loss of IL-1Ra (through deletion, truncating, or binding-null mutations) causes unrestrained IL-1 signaling leading to severe autoinflammatory disease (DIRA), while IL-1Ra promotes EC proliferation, suppresses the SASP in keratinocytes, regulates osteoblast differentiation via an ITGB3/beta-catenin interaction, and modulates lung inflammation resolution through the IL-17A/G-CSF axis; IL1RN expression is regulated transcriptionally by GATA-1 (at the rs4251961 promoter SNP) and ELF4, and post-transcriptionally by miR-125a-5p and miR-122-5p targeting, with functional genetic variants that alter mRNA levels and plasma IL-1Ra protein abundance influencing susceptibility to ARDS, septic shock, pulmonary fibrosis, and other inflammatory conditions."},"narrative":{"mechanistic_narrative":"IL1RN encodes interleukin-1 receptor antagonist (IL-1Ra), a competitive inhibitor of IL-1 signaling whose loss removes the brake on IL-1-driven inflammation [PMID:19494219, PMID:22127713]. Homozygous deletion of the IL1RN locus causes the severe autoinflammatory disease DIRA, in which patient mononuclear cells overproduce inflammatory cytokines and symptoms are completely reversed by recombinant IL-1Ra (anakinra) [PMID:19494219]; an in-frame deletion that abolishes IL-1 receptor binding reproduces the cytokine oversecretion phenotype, establishing that receptor occupancy is the basis of IL-1Ra's anti-inflammatory function [PMID:22127713]. In Il1rn-deficient mice, unrestrained IL-1 signaling directly activates keratinocytes to make TNF and chemokines, producing T-cell-independent psoriasis-like dermatitis that requires TNF from skin-resident cells [PMID:20610641], and delays resolution of acute lung inflammation by acting upstream of an IL-17A/G-CSF axis driven by gamma-delta T cells [PMID:22592923]. Beyond antagonizing secreted IL-1, an intracellular isoform (icIL-1RA1) restrains the senescence-associated secretory phenotype in keratinocytes [PMID:33526711], and IL-1Ra additionally promotes osteoblast differentiation through an integrin-beta3/beta-catenin interaction [PMID:33493267] and supports endothelial cell replicative capacity [PMID:12764021]. IL1RN expression is set transcriptionally by GATA-1 at the rs4251961 promoter SNP [PMID:21248262] and by ELF4 [PMID:38022496], and post-transcriptionally by miR-125a-5p and miR-122-5p targeting its 3'UTR [PMID:38875998, PMID:34594415]; functional coding and regulatory variants that alter mRNA and plasma IL-1Ra abundance modulate susceptibility to ARDS, septic shock, and pulmonary fibrosis [PMID:23449693, PMID:25089931, PMID:22322675].","teleology":[{"year":1993,"claim":"Establishing where IL1RN sits in the genome placed it within the interleukin-1 gene family, framing it as a paralog-derived modulator of IL-1 biology.","evidence":"Cell hybrid panel, family linkage, and FISH with a YAC probe localizing IL1RN to chromosome 2q14","pmids":["1386337","8432529"],"confidence":"Medium","gaps":["Genomic mapping does not define protein function or mechanism","Does not address how the gene is regulated or which cells express it"]},{"year":2011,"claim":"Human loss-of-function genetics resolved the question of whether IL-1Ra is physiologically required to restrain IL-1, showing that its absence or inability to bind receptor causes unchecked IL-1 signaling and severe autoinflammation.","evidence":"Homozygous IL1RN deletion in DIRA patients with ex vivo cytokine assays and anakinra rescue, plus an in-frame deletion yielding a receptor-binding-null mutant tested in vitro and in patient cells","pmids":["19494219","22127713"],"confidence":"High","gaps":["Defines requirement but not the structural basis of receptor antagonism","Does not address tissue-specific or intracellular roles of IL-1Ra"]},{"year":2012,"claim":"Mouse knockout studies defined the cellular pathways through which IL-1Ra loss drives organ-specific inflammation, mapping IL-1 to keratinocyte TNF in skin and to an IL-17A/G-CSF axis in lung resolution.","evidence":"Il1rn-/- mice with cytokine knockout crosses, adoptive transfer, bone marrow transplantation, aerosolized LPS, and IL-17A antibody blockade","pmids":["20610641","22592923"],"confidence":"High","gaps":["Downstream effectors mapped in mouse may differ across human tissues","Does not establish the molecular step at which IL-1Ra sets each threshold"]},{"year":2014,"claim":"Genetic and human-challenge studies tied specific IL1RN variants to plasma IL-1Ra abundance and clinical outcome, showing that variation acting at the mRNA level modulates susceptibility to ARDS, septic shock, and fibrosis.","evidence":"Multi-cohort association studies with paired plasma IL-1Ra ELISA, allelic imbalance by RNA-seq of adipose tissue, human LPS endotoxin challenge, and genotype-stratified mRNA analysis","pmids":["23449693","25089931","22322675"],"confidence":"High","gaps":["Variant-to-expression mechanism not resolved for synonymous rs315952 at the molecular level","Effect sizes and replication vary by clinical condition"]},{"year":2021,"claim":"Functional studies expanded IL-1Ra beyond receptor antagonism, identifying intracellular SASP suppression, an osteogenic integrin-beta3/beta-catenin role, and endothelial proliferative support.","evidence":"CRISPR knockdown of icIL-1RA1 in keratinocytes with cytokine/senescence readouts, gain/loss-of-function in osteoblast lines with ITGB3 interaction, and genotype-stratified endothelial cultures with IL-1Ra supplementation","pmids":["33526711","33493267","12764021"],"confidence":"Medium","gaps":["Single-lab findings for each non-canonical role","Mechanistic link between intracellular IL-1Ra and SASP not fully defined","ITGB3 interaction not structurally characterized"]},{"year":2023,"claim":"Regulatory studies established how IL1RN expression is controlled, identifying transcriptional activators (GATA-1, ELF4) and microRNA repressors (miR-125a-5p, miR-122-5p) that tune IL-1Ra levels and inflammatory tone.","evidence":"Promoter-reporter assays with GATA-1, ChIP and luciferase for ELF4, and dual-luciferase 3'UTR validation for miR-125a-5p and miR-122-5p with in vivo disease models","pmids":["21248262","38022496","38875998","34594415"],"confidence":"Medium","gaps":["Regulators identified in separate disease contexts, not integrated","Relative contribution of each regulator to physiological IL-1Ra levels unknown"]},{"year":2023,"claim":"Cancer studies positioned IL1RN/IL-1Ra as a modulator of the tumor immune microenvironment and tumor cell proliferation.","evidence":"Methionine-deprivation and knockdown in glioma with cell cycle analysis, and KRAS-mutant iCCA mouse models with isoform overexpression, anakinra, and anti-PD-1 combination","pmids":["30978442","37486241"],"confidence":"Medium","gaps":["Tumor-context roles are single-study and tumor-type specific","Mechanism linking IL1RN to glioma cell cycle arrest not defined"]},{"year":null,"claim":"How the canonical secreted antagonist, the intracellular isoforms, and the integrin/beta-catenin signaling activity are mechanistically partitioned within a single tissue remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling receptor antagonism with intracellular and pro-differentiation roles","Structural basis of IL-1Ra receptor binding versus ITGB3 binding not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,4,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,11]}],"complexes":[],"partners":["IL1R1","ITGB3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P18510","full_name":"Interleukin-1 receptor antagonist protein","aliases":["ICIL-1RA","IL1 inhibitor"],"length_aa":177,"mass_kda":20.1,"function":"Anti-inflammatory antagonist of interleukin-1 family of proinflammatory cytokines such as interleukin-1beta/IL1B and interleukin-1alpha/IL1A. Protects from immune dysregulation and uncontrolled systemic inflammation triggered by IL1 for a range of innate stimulatory agents such as pathogens","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P18510/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL1RN","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL1RN","total_profiled":1310},"omim":[{"mim_id":"617071","title":"LONG NONCODING RNA 13","url":"https://www.omim.org/entry/617071"},{"mim_id":"615296","title":"INTERLEUKIN 1 FAMILY, MEMBER 10; IL1F10","url":"https://www.omim.org/entry/615296"},{"mim_id":"614204","title":"PSORIASIS 14, PUSTULAR; PSORS14","url":"https://www.omim.org/entry/614204"},{"mim_id":"613659","title":"GASTRIC CANCER","url":"https://www.omim.org/entry/613659"},{"mim_id":"612852","title":"CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS 2, WITH PERIOSTITIS AND PUSTULOSIS; CRMO2","url":"https://www.omim.org/entry/612852"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Centrosome","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":1886.8}],"url":"https://www.proteinatlas.org/search/IL1RN"},"hgnc":{"alias_symbol":["IL1RA","ICIL-1RA","IL1F3","IRAP","IL-1RN","MGC10430"],"prev_symbol":[]},"alphafold":{"accession":"P18510","domains":[{"cath_id":"2.80.10.50","chopping":"37-176","consensus_level":"high","plddt":96.3915,"start":37,"end":176}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P18510","model_url":"https://alphafold.ebi.ac.uk/files/AF-P18510-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P18510-F1-predicted_aligned_error_v6.png","plddt_mean":87.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL1RN","jax_strain_url":"https://www.jax.org/strain/search?query=IL1RN"},"sequence":{"accession":"P18510","fasta_url":"https://rest.uniprot.org/uniprotkb/P18510.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P18510/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P18510"}},"corpus_meta":[{"pmid":"9519856","id":"PMC_9519856","title":"Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1beta production in vitro.","date":"1998","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9519856","citation_count":479,"is_preprint":false},{"pmid":"19494219","id":"PMC_19494219","title":"An autoinflammatory disease due to homozygous deletion of the IL1RN locus.","date":"2009","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19494219","citation_count":299,"is_preprint":false},{"pmid":"15579481","id":"PMC_15579481","title":"Genetic polymorphisms of interleukin (IL)-1B, IL-1RN, IL-8, IL-10 and tumor necrosis factor {alpha} and risk of gastric cancer in a Chinese population.","date":"2004","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/15579481","citation_count":183,"is_preprint":false},{"pmid":"1386337","id":"PMC_1386337","title":"The human IL-1 receptor antagonist gene (IL1RN) maps to chromosome 2q14-q21, in the region of the IL-1 alpha and IL-1 beta loci.","date":"1992","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/1386337","citation_count":147,"is_preprint":false},{"pmid":"8786086","id":"PMC_8786086","title":"Interleukin-1 receptor antagonist allele (IL1RN*2) associated with nephropathy in diabetes mellitus.","date":"1996","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8786086","citation_count":131,"is_preprint":false},{"pmid":"15540224","id":"PMC_15540224","title":"Role of the polymorphic IL-1B, IL-1RN and TNF-A genes in distal gastric cancer in Mexico.","date":"2005","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/15540224","citation_count":104,"is_preprint":false},{"pmid":"15190266","id":"PMC_15190266","title":"Extended haplotypes and linkage disequilibrium in the IL1R1-IL1A-IL1B-IL1RN gene cluster: association with knee osteoarthritis.","date":"2004","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/15190266","citation_count":104,"is_preprint":false},{"pmid":"35132073","id":"PMC_35132073","title":"Single-cell RNA sequencing identifies an Il1rn+/Trem1+ macrophage subpopulation as a cellular target for mitigating the progression of thoracic aortic aneurysm and dissection.","date":"2022","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35132073","citation_count":86,"is_preprint":false},{"pmid":"16907768","id":"PMC_16907768","title":"IL-1RN gene polymorphism is associated with peri-implantitis.","date":"2006","source":"Clinical oral implants research","url":"https://pubmed.ncbi.nlm.nih.gov/16907768","citation_count":82,"is_preprint":false},{"pmid":"22127713","id":"PMC_22127713","title":"A novel mutation of IL1RN in the deficiency of interleukin-1 receptor antagonist syndrome: description of two unrelated cases from Brazil.","date":"2011","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/22127713","citation_count":74,"is_preprint":false},{"pmid":"11846196","id":"PMC_11846196","title":"Smoking and polymorphisms of the interleukin-1 gene cluster (IL-1alpha, IL-1beta, and IL-1RN) in patients with periodontal disease.","date":"2002","source":"Journal of periodontology","url":"https://pubmed.ncbi.nlm.nih.gov/11846196","citation_count":73,"is_preprint":false},{"pmid":"24089414","id":"PMC_24089414","title":"Activation of human mesenchymal stem cells impacts their therapeutic abilities in lung injury by increasing interleukin (IL)-10 and IL-1RN levels.","date":"2013","source":"Stem cells translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24089414","citation_count":71,"is_preprint":false},{"pmid":"18451331","id":"PMC_18451331","title":"Polymorphisms of the IL1-receptor antagonist gene (IL1RN) are associated with multiple markers of systemic inflammation.","date":"2008","source":"Arteriosclerosis, thrombosis, and 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pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/30968643","citation_count":16,"is_preprint":false},{"pmid":"30978442","id":"PMC_30978442","title":"IL1RN mediates the suppressive effect of methionine deprivation on glioma proliferation.","date":"2019","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30978442","citation_count":15,"is_preprint":false},{"pmid":"38022496","id":"PMC_38022496","title":"The transcription factor ELF4 alleviates inflammatory bowel disease by activating IL1RN transcription, suppressing inflammatory TH17 cell activity, and inducing macrophage M2 polarization.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38022496","citation_count":15,"is_preprint":false},{"pmid":"18332090","id":"PMC_18332090","title":"Interleukin-1 receptor antagonist gene (IL-1RN) polymorphism is a predictive factor of clinical pregnancy after IVF.","date":"2008","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18332090","citation_count":15,"is_preprint":false},{"pmid":"34594415","id":"PMC_34594415","title":"miR-122-5p downregulation attenuates lipopolysaccharide-induced acute lung injury by targeting IL1RN.","date":"2021","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34594415","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":59305,"output_tokens":4853,"usd":0.125355,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13117,"output_tokens":3112,"usd":0.071693,"stage2_stop_reason":"end_turn"},"total_usd":0.197048,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"IL1RN gene maps to chromosome 2q14-q21, in the same region as IL-1alpha and IL-1beta loci, consistent with an early gene duplication event creating an interleukin-1 gene family.\",\n      \"method\": \"Somatic rodent-human cell hybrid panel analysis and linkage analysis in CEPH families using a length variation polymorphism in intron 2\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromosomal mapping by cell hybrid panel and family linkage, two orthogonal approaches in one study\",\n      \"pmids\": [\"1386337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The human IL1RN gene was localized to chromosome 2q14.2 by fluorescence in situ hybridization using a yeast artificial chromosome containing IL1RN as a probe, near the IL-1alpha, IL-1beta, and IL-1 receptor genes.\",\n      \"method\": \"FISH with YAC probe; Southern blot of human-Chinese hamster cell hybrids\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal localization methods (FISH + Southern blot of hybrid cells), single study\",\n      \"pmids\": [\"8432529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Homozygous deletion of the IL1RN locus (175-kb deletion at chromosome 2q13) causes a severe autoinflammatory disease (DIRA) characterized by pustular rash, lytic bone lesions, osteopenia, respiratory insufficiency, and thrombosis; mononuclear cells from the patient produced markedly elevated inflammatory cytokines, and treatment with anakinra (recombinant IL-1Ra) completely resolved symptoms, establishing that absence of IL-1Ra protein causes unchecked IL-1 signaling.\",\n      \"method\": \"Genetic analysis (homozygous deletion identified), ex vivo cytokine production assay of patient mononuclear cells, therapeutic rescue with anakinra\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human loss-of-function genetic variant with defined cellular phenotype (excess cytokine production) and therapeutic rescue, replicated across multiple DIRA reports\",\n      \"pmids\": [\"19494219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A novel homozygous 15-bp in-frame deletion in IL1RN produces a mutant IL-1Ra protein that has no affinity for the IL-1 receptor in vitro, and patient cells stimulated with IL-1alpha or IL-1beta showed oversecretion of proinflammatory cytokines, demonstrating that receptor binding is required for IL-1Ra's anti-inflammatory function.\",\n      \"method\": \"In vitro expression of mutant protein with IL-1 receptor binding assay; stimulation of patient cells with recombinant IL-1alpha/IL-1beta and cytokine measurement\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro receptor binding assay with mutant protein plus functional cell assay in patient-derived cells, single lab with two orthogonal methods\",\n      \"pmids\": [\"22127713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In Il1rn-/- mice, spontaneous psoriasis-like dermatitis is driven by excess IL-1 signaling that directly activates keratinocytes to produce TNF and chemokines; development of dermatitis requires TNF (completely suppressed in Tnfsf1a-/- mice) but not IL-6 or IL-17, and is T-cell independent (lesions develop in Il1rn-/- SCID mice; adoptive transfer of Il1rn-/- T cells does not induce dermatitis). Bone marrow transplantation showed that TNF from skin-resident (non-bone marrow-derived) cells is critical.\",\n      \"method\": \"Genetic knockout mice (Il1rn-/-, Tnfsf1a-/-, Il6-/-, IL-17-deficient crosses); adoptive transfer experiments into SCID mice; bone marrow transplantation; cytokine/chemokine measurement at inflammation site\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic approaches (KO crosses, adoptive transfer, BMT), defining both the pathway (IL-1 → keratinocyte TNF) and the cell type responsible\",\n      \"pmids\": [\"20610641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In Il1rn-/- mice exposed to aerosolized LPS, resolution of lung inflammation is delayed relative to wild-type, with increased BAL neutrophils, elevated IL-17A expression (from gamma-delta T cells), and elevated G-CSF. Blockade of IL-17A reduced BAL neutrophil counts and lung G-CSF expression in Il1rn-/- mice, placing IL-1Ra upstream of the IL-17A/G-CSF axis in resolution of acute lung inflammation.\",\n      \"method\": \"Knockout mouse model (Il1rn-/-) with aerosolized LPS; BAL cell counts and protein measurement; cytokine/RNA profiling; IL-17A monoclonal antibody blockade\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype, pathway placed by antibody blockade, two orthogonal intervention methods\",\n      \"pmids\": [\"22592923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The IL1RN promoter SNP rs4251961 (C allele) is associated with increased plasma IL-1Ra concentrations during invasive pneumococcal disease. Functional reporter assays in HEK293T cells showed that the C allele promoter construct has ~9-fold increased activity versus ~6-fold for the T allele in the presence of GATA-1, identifying GATA-1 as a differential transcriptional regulator of IL1RN expression at this locus.\",\n      \"method\": \"Promoter-reporter (luciferase) transfection assay in HEK293T cells with and without GATA-1 overexpression; plasma IL-1Ra measurement in 299 children with invasive pneumococcal disease; validation in HIV-infected adult cohort\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter assay with transcription factor co-transfection plus in vivo correlation in two independent cohorts, single lab\",\n      \"pmids\": [\"21248262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The IL1RN coding variant rs315952C is associated with decreased risk of ARDS in three independent populations; carriers of rs315952C have higher plasma IL-1Ra levels, establishing that this synonymous variant functionally influences IL1Ra protein levels and thereby modulates ARDS susceptibility.\",\n      \"method\": \"Multi-stage genetic association study (three critically ill cohorts, n=3065 total); ELISA for plasma IL-1Ra protein levels stratified by genotype\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated in three independent populations with paired protein level measurement, demonstrating functional consequence of the variant\",\n      \"pmids\": [\"23449693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The IL1RN synonymous coding variant rs315952C is preferentially transcribed (allelic imbalance demonstrated by RNA sequencing of adipose tissue), leading to higher evoked plasma IL-1Ra after LPS challenge and improved survival in septic shock, establishing that this variant acts at the level of mRNA expression to modulate IL-1Ra protein levels and downstream clinical outcomes.\",\n      \"method\": \"RNA sequencing of adipose tissue for allelic imbalance; human LPS endotoxin challenge model (n=294 volunteers) with plasma IL-1Ra ELISA; genetic association study for survival in the VASST septic shock cohort\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — allelic imbalance by RNA-seq provides mechanistic basis; validated in controlled human LPS model and independent septic shock cohort\",\n      \"pmids\": [\"25089931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The IL1RN VNTR*2 haploblock is associated with IPF susceptibility, and the IL1RN SNP rs2637988 significantly influences IL-1Ra mRNA expression levels (carriers of the minor GG genotype have lower mRNA), suggesting that reduced IL-1Ra expression predisposes to pulmonary fibrosis.\",\n      \"method\": \"Meta-analysis of five case-control studies; IL1RN mRNA expression analysis correlated with genotype in patient samples\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mRNA expression-genotype correlation in patient samples with meta-analysis replication, but no direct functional manipulation\",\n      \"pmids\": [\"22322675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Intracellular IL-1RA type 1 (icIL-1RA1, a product of IL1RN) is progressively lost during oral carcinogenesis; CRISPR/Cas9-mediated knockdown of icIL-1RA1 in normal and dysplastic oral keratinocytes caused increased IL-6 and IL-8 secretion and accelerated senescence, establishing icIL-1RA1 as a regulator of the senescence-associated secretory phenotype (SASP).\",\n      \"method\": \"CRISPR/Cas9 knockdown in primary keratinocytes; IL-6/IL-8 ELISA; senescence assay; ex vivo tissue expression analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR loss-of-function with defined cytokine phenotype, single lab\",\n      \"pmids\": [\"33526711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL1RN promotes osteoblast differentiation by interacting with integrin beta3 (ITGB3) to activate beta-catenin signaling; silencing IL1RN attenuated osteogenic differentiation while overexpression increased alkaline phosphatase, osterix, and osteocalcin expression in MC3T3-E1 and C3H10T1/2 cells.\",\n      \"method\": \"IL1RN knockdown and overexpression in osteoblast cell lines; co-interaction assay with ITGB3; osteogenic staining; Western blot for osteogenic markers and beta-catenin pathway components\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — gain- and loss-of-function with pathway readout, interaction with ITGB3 identified, single lab\",\n      \"pmids\": [\"33493267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL1RN mediates the suppressive effect of methionine deprivation on glioma cell proliferation; methionine deprivation or IL1RN knockdown induced glioma cell cycle arrest both in vitro and in vivo.\",\n      \"method\": \"Methionine deprivation experiments in glioma cell lines; IL1RN knockdown; cell cycle analysis; in vivo tumor model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal interventions (metabolic deprivation + gene knockdown) with defined cell cycle phenotype, single lab\",\n      \"pmids\": [\"30978442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In KRAS-mutant intrahepatic cholangiocarcinoma, alternative splicing upregulates IL1RN-201/203 isoforms as a negative feedback mechanism; both IL1RN-201/203 upregulation and anakinra treatment altered neutrophil recruitment/phenotypes and activated intratumoral GZMB+ CD8+ T cells, and synergized with anti-PD-1 therapy in KRAS-mutant iCCA mouse models.\",\n      \"method\": \"Multiomics analysis of patient samples; in vivo KRAS-mutant iCCA mouse models with IL1RN isoform overexpression and anakinra treatment; flow cytometry for immune cell phenotyping; combination with anti-PD-1\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model with genetic and pharmacologic interventions, immune phenotyping, single study\",\n      \"pmids\": [\"37486241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Exosomal miR-125a-5p from cigarette smoke-exposed bronchial epithelial cells is taken up by macrophages and targets IL1RN (confirmed by luciferase reporter assay), reducing IL-1Ra expression and promoting M1 macrophage polarization via the MyD88/NF-κB pathway.\",\n      \"method\": \"Luciferase reporter assay for miR-125a-5p targeting of IL1RN 3'UTR; PKH26-labeled exosome uptake; co-culture of epithelial cells and macrophages; miR-125a-5p mimic/inhibitor transfection; in vivo COPD mouse model with miR-125a-5p inhibitor\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation by luciferase assay plus in vivo rescue, single lab\",\n      \"pmids\": [\"38875998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-122-5p directly targets IL1RN (confirmed by TargetScan prediction and dual luciferase reporter assay); miR-122-5p mimics decreased cell viability and promoted apoptosis/inflammation in LPS-treated A549 cells, and these effects were reversed by IL1RN siRNA knockdown, establishing IL1RN as a functional target of miR-122-5p in LPS-induced lung injury.\",\n      \"method\": \"Dual luciferase reporter gene assay; miR-122-5p mimic/inhibitor transfection; IL1RN siRNA; LPS-induced ALI cell model; ELISA for TNF-alpha, IL-1beta, IL-6\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase assay for direct targeting plus epistasis rescue experiment, single lab\",\n      \"pmids\": [\"34594415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The transcription factor ELF4 activates IL1RN transcription; dual-luciferase and ChIP assays in BMDMs and intestinal epithelial cells demonstrated ELF4 binding to the IL1RN promoter and increased IL1RN promoter activity. ELF4-driven IL1RN upregulation suppressed inflammatory TH17 cell activity and induced macrophage M2 polarization to alleviate experimental colitis.\",\n      \"method\": \"Dual-luciferase reporter assay; ChIP assay; ELF4 overexpression in vivo (LPS-induced colitis mouse model); flow cytometry for macrophage polarization and TH17 cells; ELISA\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase assays establish direct ELF4-IL1RN promoter interaction, functional in vivo rescue, single lab\",\n      \"pmids\": [\"38022496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The IL-1RN*2/*2 genotype is associated with decreased endothelial cell (EC) cumulative population doublings and reduced proliferation at later passage, with increased senescent ECs. Addition of exogenous IL-1Ra (1 ng/mL) increased proliferation of IL-1RN*2/*2 ECs, suggesting that IL-1Ra promotes EC replicative capacity.\",\n      \"method\": \"Ex vivo EC culture from human donors stratified by IL-1RN genotype; Ki67 proliferation assay; cumulative population doubling counts; exogenous IL-1Ra supplementation\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genotype-stratified functional assay with pharmacological rescue, single lab with multiple readouts\",\n      \"pmids\": [\"12764021\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL1RN encodes interleukin-1 receptor antagonist (IL-1Ra), a secreted and intracellular protein that competitively inhibits IL-1alpha and IL-1beta binding to the IL-1 receptor; loss of IL-1Ra (through deletion, truncating, or binding-null mutations) causes unrestrained IL-1 signaling leading to severe autoinflammatory disease (DIRA), while IL-1Ra promotes EC proliferation, suppresses the SASP in keratinocytes, regulates osteoblast differentiation via an ITGB3/beta-catenin interaction, and modulates lung inflammation resolution through the IL-17A/G-CSF axis; IL1RN expression is regulated transcriptionally by GATA-1 (at the rs4251961 promoter SNP) and ELF4, and post-transcriptionally by miR-125a-5p and miR-122-5p targeting, with functional genetic variants that alter mRNA levels and plasma IL-1Ra protein abundance influencing susceptibility to ARDS, septic shock, pulmonary fibrosis, and other inflammatory conditions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL1RN encodes interleukin-1 receptor antagonist (IL-1Ra), a competitive inhibitor of IL-1 signaling whose loss removes the brake on IL-1-driven inflammation [#2, #3]. Homozygous deletion of the IL1RN locus causes the severe autoinflammatory disease DIRA, in which patient mononuclear cells overproduce inflammatory cytokines and symptoms are completely reversed by recombinant IL-1Ra (anakinra) [#2]; an in-frame deletion that abolishes IL-1 receptor binding reproduces the cytokine oversecretion phenotype, establishing that receptor occupancy is the basis of IL-1Ra's anti-inflammatory function [#3]. In Il1rn-deficient mice, unrestrained IL-1 signaling directly activates keratinocytes to make TNF and chemokines, producing T-cell-independent psoriasis-like dermatitis that requires TNF from skin-resident cells [#4], and delays resolution of acute lung inflammation by acting upstream of an IL-17A/G-CSF axis driven by gamma-delta T cells [#5]. Beyond antagonizing secreted IL-1, an intracellular isoform (icIL-1RA1) restrains the senescence-associated secretory phenotype in keratinocytes [#10], and IL-1Ra additionally promotes osteoblast differentiation through an integrin-beta3/beta-catenin interaction [#11] and supports endothelial cell replicative capacity [#17]. IL1RN expression is set transcriptionally by GATA-1 at the rs4251961 promoter SNP [#6] and by ELF4 [#16], and post-transcriptionally by miR-125a-5p and miR-122-5p targeting its 3'UTR [#14, #15]; functional coding and regulatory variants that alter mRNA and plasma IL-1Ra abundance modulate susceptibility to ARDS, septic shock, and pulmonary fibrosis [#7, #8, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing where IL1RN sits in the genome placed it within the interleukin-1 gene family, framing it as a paralog-derived modulator of IL-1 biology.\",\n      \"evidence\": \"Cell hybrid panel, family linkage, and FISH with a YAC probe localizing IL1RN to chromosome 2q14\",\n      \"pmids\": [\"1386337\", \"8432529\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genomic mapping does not define protein function or mechanism\", \"Does not address how the gene is regulated or which cells express it\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Human loss-of-function genetics resolved the question of whether IL-1Ra is physiologically required to restrain IL-1, showing that its absence or inability to bind receptor causes unchecked IL-1 signaling and severe autoinflammation.\",\n      \"evidence\": \"Homozygous IL1RN deletion in DIRA patients with ex vivo cytokine assays and anakinra rescue, plus an in-frame deletion yielding a receptor-binding-null mutant tested in vitro and in patient cells\",\n      \"pmids\": [\"19494219\", \"22127713\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Defines requirement but not the structural basis of receptor antagonism\", \"Does not address tissue-specific or intracellular roles of IL-1Ra\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mouse knockout studies defined the cellular pathways through which IL-1Ra loss drives organ-specific inflammation, mapping IL-1 to keratinocyte TNF in skin and to an IL-17A/G-CSF axis in lung resolution.\",\n      \"evidence\": \"Il1rn-/- mice with cytokine knockout crosses, adoptive transfer, bone marrow transplantation, aerosolized LPS, and IL-17A antibody blockade\",\n      \"pmids\": [\"20610641\", \"22592923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors mapped in mouse may differ across human tissues\", \"Does not establish the molecular step at which IL-1Ra sets each threshold\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genetic and human-challenge studies tied specific IL1RN variants to plasma IL-1Ra abundance and clinical outcome, showing that variation acting at the mRNA level modulates susceptibility to ARDS, septic shock, and fibrosis.\",\n      \"evidence\": \"Multi-cohort association studies with paired plasma IL-1Ra ELISA, allelic imbalance by RNA-seq of adipose tissue, human LPS endotoxin challenge, and genotype-stratified mRNA analysis\",\n      \"pmids\": [\"23449693\", \"25089931\", \"22322675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Variant-to-expression mechanism not resolved for synonymous rs315952 at the molecular level\", \"Effect sizes and replication vary by clinical condition\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Functional studies expanded IL-1Ra beyond receptor antagonism, identifying intracellular SASP suppression, an osteogenic integrin-beta3/beta-catenin role, and endothelial proliferative support.\",\n      \"evidence\": \"CRISPR knockdown of icIL-1RA1 in keratinocytes with cytokine/senescence readouts, gain/loss-of-function in osteoblast lines with ITGB3 interaction, and genotype-stratified endothelial cultures with IL-1Ra supplementation\",\n      \"pmids\": [\"33526711\", \"33493267\", \"12764021\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings for each non-canonical role\", \"Mechanistic link between intracellular IL-1Ra and SASP not fully defined\", \"ITGB3 interaction not structurally characterized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Regulatory studies established how IL1RN expression is controlled, identifying transcriptional activators (GATA-1, ELF4) and microRNA repressors (miR-125a-5p, miR-122-5p) that tune IL-1Ra levels and inflammatory tone.\",\n      \"evidence\": \"Promoter-reporter assays with GATA-1, ChIP and luciferase for ELF4, and dual-luciferase 3'UTR validation for miR-125a-5p and miR-122-5p with in vivo disease models\",\n      \"pmids\": [\"21248262\", \"38022496\", \"38875998\", \"34594415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Regulators identified in separate disease contexts, not integrated\", \"Relative contribution of each regulator to physiological IL-1Ra levels unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cancer studies positioned IL1RN/IL-1Ra as a modulator of the tumor immune microenvironment and tumor cell proliferation.\",\n      \"evidence\": \"Methionine-deprivation and knockdown in glioma with cell cycle analysis, and KRAS-mutant iCCA mouse models with isoform overexpression, anakinra, and anti-PD-1 combination\",\n      \"pmids\": [\"30978442\", \"37486241\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tumor-context roles are single-study and tumor-type specific\", \"Mechanism linking IL1RN to glioma cell cycle arrest not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the canonical secreted antagonist, the intracellular isoforms, and the integrin/beta-catenin signaling activity are mechanistically partitioned within a single tissue remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling receptor antagonism with intracellular and pro-differentiation roles\", \"Structural basis of IL-1Ra receptor binding versus ITGB3 binding not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 4, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IL1R1\",\n      \"ITGB3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}