{"gene":"IL36A","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2001,"finding":"IL-1F6 (later renamed IL-36α) activates NF-κB signaling through the orphan receptor IL-1Rrp2 (IL-1R-related protein 2), while the closely related IL-1F5 (IL-36Ra) specifically and potently inhibits this IL-1F6/IL-36α response, establishing an independent agonist/antagonist signaling system at IL-1Rrp2.","method":"NF-κB–luciferase reporter assays in transfected cell lines; IL-1F5 antagonism of IL-1F6-induced NF-κB activation","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 — functional reporter assay with receptor transfection and antagonist blocking; replicated in subsequent studies","pmids":["11466363"],"is_preprint":false},{"year":2000,"finding":"IL-36α (designated FIL1ε) was cloned as a novel IL-1 family member; protein structure modeling predicts a beta-barrel fold shared with IL-1β/IL-1Ra, and the gene maps to the IL-1 cluster on human chromosome 2q.","method":"EST database searches, cDNA cloning, protein structure modeling, chromosomal mapping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — initial cloning and structural prediction without functional assay","pmids":["10625660"],"is_preprint":false},{"year":2000,"finding":"IL-36α (designated IL-1H1) is constitutively expressed in placenta and squamous epithelium of the esophagus, and can be induced in keratinocytes by IFN-γ and TNF-α in vitro and by contact hypersensitivity or herpes simplex virus infection in vivo, suggesting a role in immune-mediated epithelial responses.","method":"Northern blot, in vitro keratinocyte stimulation, in vivo contact hypersensitivity and HSV infection models","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2/3 — direct induction experiments in vitro and in vivo, single lab","pmids":["10744718"],"is_preprint":false},{"year":2004,"finding":"IL-36α (IL-1F6), IL-36β (IL-1F8), and IL-36γ (IL-1F9) all signal through both IL-1Rrp2 and IL-1RAcP to activate the NF-κB pathway and MAPKs (JNK and ERK1/2), and downstream targets including an IL-8 promoter and IL-6 secretion. Antibodies to IL-1Rrp2 block signaling, and cytoplasmically-deleted IL-1RAcP acts as a dominant negative, establishing IL-1RAcP as an essential co-receptor.","method":"NF-κB reporter assays, receptor transfection, neutralizing antibodies to IL-1Rrp2, dominant-negative IL-1RAcP transfection, MAPK Western blotting, IL-6/IL-8 secretion assays in multiple cell lines","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (reporter, dominant-negative, antibody block), multiple cell lines, strong mechanistic conclusions","pmids":["14734551"],"is_preprint":false},{"year":2007,"finding":"Transgenic expression of IL-1F6 (IL-36α) in basal keratinocytes in mice caused skin inflammation (acanthosis, hyperkeratosis, mixed inflammatory infiltrate, elevated cytokines/chemokines) in an IL-1Rrp2– and IL-1RAcP–dependent manner. Genetic deletion of IL-1F5 (IL-36Ra) in these mice exacerbated the phenotype, providing in vivo genetic evidence that IL-1F5 is a functional antagonist of IL-1F6/IL-36α.","method":"Transgenic mouse generation, genetic epistasis (IL-1F6 transgene × IL-1F5 knockout), histopathology, cytokine/chemokine expression analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic epistasis with receptor-dependence confirmed by double-transgenic/knockout crosses","pmids":["17908936"],"is_preprint":false},{"year":2011,"finding":"Full agonist activity of IL-36α (IL-1F6) requires N-terminal truncation to remove a prodomain; truncated IL-36α has ~10³–10⁴-fold greater specific activity (EC₅₀ shifting from ~1 μg/ml to ~1 ng/ml), demonstrating that post-translational proteolytic processing is required for full IL-36α activity.","method":"N-terminal truncation series of recombinant proteins, NF-κB reporter assays comparing full-length vs. truncated forms","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — systematic in vitro reconstitution with defined truncation series and quantitative dose-response; replicated across multiple IL-36 family members","pmids":["21965679"],"is_preprint":false},{"year":2011,"finding":"IL-36α (IL-1F6) and related IL-1F cytokines are markedly upregulated in psoriatic skin (2–3 orders of magnitude vs. uninvolved skin), and are induced in normal keratinocytes by IL-1α and TNF-α. IL-36α and IL-1F8 induce expression of antimicrobial peptides (HBD-2, HBD-3, CAMP) and matrix metalloproteinases in reconstituted human epidermis.","method":"Quantitative RT-PCR, immunohistochemistry, in vitro keratinocyte stimulation, reconstituted human epidermis model, microarray analysis","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2–3 — functional assays in keratinocyte models but primarily correlative in human tissue; mechanistic output (antimicrobial peptide induction) experimentally demonstrated","pmids":["21242515"],"is_preprint":false},{"year":2012,"finding":"IL-36α is expressed by CD138+ plasma cells in psoriatic arthritis and rheumatoid arthritis synovium. Recombinant IL-36α activates synovial fibroblasts (FLS) to produce IL-6 and IL-8 through p38 MAPK and NF-κB signaling pathways.","method":"Immunohistochemistry, immunofluorescence, Western blot, quantitative RT-PCR, multiplex cytokine assay, immunoblotting for p38/NF-κB activation in FLS","journal":"Annals of the rheumatic diseases","confidence":"Medium","confidence_rationale":"Tier 2–3 — receptor-ligand functional assay with signaling pathway validation in primary FLS, single lab","pmids":["23268368"],"is_preprint":false},{"year":2014,"finding":"Intradermal injection of IL-36α in mice induces chemokine expression (CXCL1, CXCL8, CCL3, CCL5, CCL20), leukocyte infiltration, and acanthosis. Blood monocytes, myeloid dendritic cells, and monocyte-derived DCs express IL-36R and respond directly to IL-36α by upregulating IL-1β and IL-6 production and DC maturation markers (CD83, CD86, HLA-DR); IL-36α–treated monocyte-derived DCs enhance allogeneic CD4+ T cell proliferation.","method":"In vivo intradermal injection, flow cytometry, ELISA, RT-PCR; in vitro monocyte/DC stimulation assays","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 — in vivo and in vitro orthogonal approaches defining cellular targets and functional consequences, replicated across multiple cell types","pmids":["24829417"],"is_preprint":false},{"year":2016,"finding":"IL-36α expression is specifically elevated in colonic mucosa of ulcerative colitis patients and in DSS colitis mice. IL-36R-deficient mice exhibit reduced disease severity in DSS colitis with decreased innate inflammatory cell infiltration, and show increased bacterial colonization and altered T helper (enhanced Th17, reduced Th1) responses upon Citrobacter rodentium infection, establishing IL-36R/IL-36α signaling as a mediator of colonic mucosal inflammation and host defense.","method":"RT-PCR on patient biopsies, DSS colitis mouse model, Citrobacter rodentium infection model, flow cytometry, IL-36R knockout mice","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function (receptor KO) with defined phenotypic readouts in two independent in vivo disease models","pmids":["26813344"],"is_preprint":false},{"year":2016,"finding":"IL-36α induces expression of CXC chemokines (CXCL1, CXCL2, CXCL3) in intestinal epithelial cells by assembling a MyD88/TRAF6/IRAK1/TAK1 signaling complex that activates NF-κB, AP-1, and MAPK phosphorylation; NF-κB and c-Jun AP-1 siRNA knockdown and MAPK inhibitors reduce IL-36α–induced chemokine expression.","method":"ELISA, Western blot, co-immunoprecipitation of signaling complex, siRNA knockdown of NF-κB/AP-1, MAPK inhibitors, RT-PCR in HT-29 cells","journal":"Inflammatory bowel diseases","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical complex assembly, genetic (siRNA) and pharmacological inhibition of pathway components, multiple orthogonal approaches","pmids":["26752465"],"is_preprint":false},{"year":2017,"finding":"IL-36γ (and by implication other IL-36 agonists including IL-36α) is secreted from keratinocytes in an inactive form and is proteolytically activated by neutrophil-derived proteases, including neutrophil elastase, which cleaves the N-terminal prodomain to generate the active truncated form. Truncated IL-36 cytokines cooperate synergistically with IL-17A to regulate keratinocyte differentiation and target gene expression.","method":"3D organotypic skin models, recombinant protein incubation with purified proteases, N-terminal sequencing, gene expression analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical demonstration of elastase-mediated activation in organotypic model; mechanistic basis for IL-36 processing in vivo","pmids":["29142248"],"is_preprint":false},{"year":2006,"finding":"IL-36α (IL-1 family member 6 / IL-1F6) was identified as a nitroprotein in human pituitary adenoma tissue by nitrotyrosine affinity chromatography and tandem mass spectrometry, demonstrating that IL-36α undergoes tyrosine nitration as a post-translational modification in vivo.","method":"Nitrotyrosine affinity column enrichment, trypsin digestion, tandem mass spectrometry","journal":"Analytical biochemistry","confidence":"Low","confidence_rationale":"Tier 3 — single MS-based detection without functional validation of the nitration","pmids":["16777052"],"is_preprint":false},{"year":2015,"finding":"High-throughput affinity-purification mass spectrometry (BioPlex) identified interaction partners for IL-36α (IL-1F6) in HEK293T cells, placing it within the human interactome network.","method":"Affinity-purification mass spectrometry (AP-MS), BioPlex network","journal":"Cell","confidence":"Low","confidence_rationale":"Tier 3 — high-throughput AP-MS without validation of specific IL-36α interactions","pmids":["26186194"],"is_preprint":false}],"current_model":"IL-36α (IL-1F6) is an IL-1 family cytokine that requires N-terminal proteolytic processing (e.g., by neutrophil elastase) for full agonist activity; the processed form signals through a heterodimeric receptor complex of IL-1Rrp2 (IL-1RL2) and IL-1RAcP, recruiting a MyD88/TRAF6/IRAK1/TAK1 signaling complex that activates NF-κB, AP-1, and MAPKs (p38, JNK, ERK1/2) to drive chemokine, IL-6, IL-8, and antimicrobial peptide production, predominantly in epithelial (keratinocyte, intestinal) and myeloid (monocyte, dendritic cell, synovial fibroblast) cell contexts; its activity is antagonized by IL-36Ra (IL-1F5), which binds IL-1Rrp2 and prevents IL-1RAcP co-recruitment."},"narrative":{"teleology":[{"year":2000,"claim":"Identification of IL-36α as a novel IL-1 family member (FIL1ε/IL-1H1) with a predicted β-barrel fold and gene localization to the IL-1 cluster on chromosome 2q established its molecular identity, while initial expression profiling revealed constitutive expression in squamous epithelium and inducibility by IFN-γ and TNF-α in keratinocytes.","evidence":"cDNA cloning, structural modeling, Northern blot, keratinocyte stimulation, and in vivo contact-hypersensitivity/HSV models","pmids":["10625660","10744718"],"confidence":"Medium","gaps":["No receptor identified at this stage","No functional activity assay performed","Protein processing requirements unknown"]},{"year":2001,"claim":"The first functional assay demonstrated that IL-36α activates NF-κB through the orphan receptor IL-1Rrp2 and that IL-36Ra (IL-1F5) specifically blocks this activation, establishing an agonist–antagonist signaling axis distinct from classical IL-1.","evidence":"NF-κB luciferase reporter assays with IL-1Rrp2 transfection and IL-1F5 antagonism","pmids":["11466363"],"confidence":"High","gaps":["Role of co-receptor (IL-1RAcP) not yet established","Downstream signaling cascades beyond NF-κB unknown"]},{"year":2004,"claim":"IL-1RAcP was identified as an essential co-receptor: dominant-negative IL-1RAcP and neutralizing anti-IL-1Rrp2 antibodies blocked IL-36α signaling, and JNK/ERK1/2 MAPK cascades were identified as additional downstream effectors alongside NF-κB, with IL-6 and IL-8 as functional outputs.","evidence":"Receptor transfection, dominant-negative IL-1RAcP, neutralizing antibodies, MAPK Western blotting, IL-6/IL-8 secretion assays in multiple cell lines","pmids":["14734551"],"confidence":"High","gaps":["Structural basis for IL-1Rrp2/IL-1RAcP heterodimerization not resolved","Requirement for N-terminal processing not yet recognized"]},{"year":2007,"claim":"In vivo genetic evidence confirmed the agonist–antagonist paradigm: transgenic IL-36α expression in mouse basal keratinocytes caused IL-1Rrp2/IL-1RAcP-dependent skin inflammation, and concurrent IL-36Ra knockout exacerbated the phenotype, proving IL-36Ra is a physiological antagonist in vivo.","evidence":"Transgenic/knockout mouse crosses with histopathology and cytokine expression analysis","pmids":["17908936"],"confidence":"High","gaps":["Endogenous protease responsible for IL-36α activation in skin not identified","Relative contribution of IL-36α vs. other IL-36 agonists in skin inflammation unclear"]},{"year":2011,"claim":"Two key advances clarified IL-36α biology: systematic N-terminal truncation showed that prodomain removal increases specific activity by 10³–10⁴-fold, explaining previously discrepant dose–response data; and IL-36α was found massively upregulated in psoriatic skin where it induces antimicrobial peptides (HBD-2, HBD-3, CAMP) in reconstituted human epidermis.","evidence":"Recombinant truncation series with quantitative NF-κB reporter dose–response; qRT-PCR on patient biopsies; reconstituted human epidermis stimulation","pmids":["21965679","21242515"],"confidence":"High","gaps":["In vivo protease responsible for N-terminal processing not yet identified","Role in psoriasis causation vs. consequence not formally tested"]},{"year":2014,"claim":"Cellular target breadth was expanded beyond epithelia: monocytes, myeloid DCs, and monocyte-derived DCs were shown to express IL-36R and respond to IL-36α by producing IL-1β and IL-6 and upregulating maturation markers; IL-36α-treated DCs enhanced CD4+ T cell proliferation, establishing a link between IL-36α and adaptive immune priming.","evidence":"In vivo intradermal injection, flow cytometry, ELISA, in vitro monocyte/DC stimulation, allogeneic T cell proliferation assays","pmids":["24829417"],"confidence":"High","gaps":["Whether IL-36α acts directly on T cells not resolved","Relative potency of IL-36α vs. IL-36β/γ on myeloid cells not compared"]},{"year":2016,"claim":"Two studies established IL-36α function in the intestinal compartment: IL-36R-deficient mice showed reduced DSS colitis severity and altered T helper polarization (enhanced Th17, reduced Th1) during Citrobacter rodentium infection; mechanistically, IL-36α assembles a MyD88/TRAF6/IRAK1/TAK1 complex in intestinal epithelial cells to activate NF-κB, AP-1, and MAPKs for CXC chemokine production.","evidence":"IL-36R knockout mice in DSS colitis and enteric infection models; co-immunoprecipitation of signaling complex, siRNA and pharmacological pathway inhibition in HT-29 cells","pmids":["26813344","26752465"],"confidence":"High","gaps":["Specific IL-36α protease in the intestinal milieu not identified","Whether IL-36α signals in intestinal immune cells independently of epithelial chemokine induction not established"]},{"year":2017,"claim":"Neutrophil elastase was identified as a physiologically relevant protease that cleaves the IL-36 prodomain to generate active cytokine, and truncated IL-36 cytokines were shown to synergize with IL-17A in regulating keratinocyte differentiation, connecting neutrophil recruitment to amplification of IL-36 signaling.","evidence":"3D organotypic skin models, incubation with purified neutrophil elastase, N-terminal sequencing, gene expression analysis","pmids":["29142248"],"confidence":"Medium","gaps":["Whether elastase is the predominant processing protease in vivo or if other proteases contribute","Structural basis of IL-36/IL-17A synergistic signaling not resolved"]},{"year":null,"claim":"Key unresolved questions include the structural basis of the IL-36α/IL-1Rrp2/IL-1RAcP ternary complex, the full repertoire of activating proteases across tissues, direct effects on lymphocyte subsets, and whether IL-36α has non-redundant functions relative to IL-36β and IL-36γ.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of IL-36α/receptor complex","Non-redundancy among IL-36 agonists not tested by individual genetic deletion","Intracellular vs. extracellular processing compartment undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,3,5,8,10]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[5,8,11]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,3,4,8,9,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,10]}],"complexes":[],"partners":["IL1RL2","IL1RAP","MYD88","TRAF6","IRAK1","MAP3K7","IL36RN"],"other_free_text":[]},"mechanistic_narrative":"IL-36α is a pro-inflammatory IL-1 family cytokine that functions as an agonist of the IL-1Rrp2/IL-1RAcP heterodimeric receptor complex to activate NF-κB, AP-1, and MAPK (p38, JNK, ERK1/2) signaling via a MyD88/TRAF6/IRAK1/TAK1 signaling module, driving production of chemokines (CXCL1, CXCL2, IL-8), IL-6, and antimicrobial peptides in keratinocytes, intestinal epithelial cells, synovial fibroblasts, and myeloid cells [PMID:14734551, PMID:26752465, PMID:24829417]. Full agonist activity requires N-terminal proteolytic removal of a prodomain—achievable by neutrophil elastase—which increases specific activity by 10³–10⁴-fold [PMID:21965679, PMID:29142248]. IL-36α activity is antagonized by IL-36Ra (IL-1F5), which binds IL-1Rrp2 and prevents IL-1RAcP co-recruitment; genetic deletion of IL-36Ra in mice expressing an IL-36α transgene exacerbates skin inflammation [PMID:11466363, PMID:17908936]. IL-36 receptor signaling promotes mucosal inflammation in colitis models and shapes T helper polarization during enteric infection, and IL-36α is markedly upregulated in psoriatic skin and inflamed colonic mucosa [PMID:26813344, PMID:21242515]."},"prefetch_data":{"uniprot":{"accession":"Q9UHA7","full_name":"Interleukin-36 alpha","aliases":["FIL1 epsilon","Interleukin-1 epsilon","IL-1 epsilon","Interleukin-1 family member 6","IL-1F6"],"length_aa":158,"mass_kda":17.7,"function":"Cytokine that binds to and signals through the IL1RL2/IL-36R receptor which in turn activates NF-kappa-B and MAPK signaling pathways in target cells linked to a pro-inflammatory response. Part of the IL-36 signaling system that is thought to be present in epithelial barriers and to take part in local inflammatory response; similar to the IL-1 system with which it shares the coreceptor IL1RAP. Seems to be involved in skin inflammatory response by acting on keratinocytes, dendritic cells and indirectly on T-cells to drive tissue infiltration, cell maturation and cell proliferation. In cultured keratinocytes induces the expression of macrophage, T-cell, and neutrophil chemokines, such as CCL3, CCL4, CCL5, CCL2, CCL17, CCL22, CL20, CCL5, CCL2, CCL17, CCL22, CXCL8, CCL20 and CXCL1, and the production of pro-inflammatory cytokines such as TNF, IL-8 and IL-6. In cultured monocytes up-regulates expression of IL-1A, IL-1B and IL-6. In myeloid dendritic cells involved in cell maturation by up-regulating surface expression of CD83, CD86 and HLA-DR. In monocyte-derived dendritic cells facilitates dendritic cell maturation and drives T-cell proliferation. May play a role in pro-inflammatory effects in the lung","subcellular_location":"Cytoplasm; Secreted","url":"https://www.uniprot.org/uniprotkb/Q9UHA7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL36A","classification":"Not Classified","n_dependent_lines":55,"n_total_lines":1208,"dependency_fraction":0.04552980132450331},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL36A","total_profiled":1310},"omim":[{"mim_id":"615296","title":"INTERLEUKIN 1 FAMILY, MEMBER 10; IL1F10","url":"https://www.omim.org/entry/615296"},{"mim_id":"605542","title":"INTERLEUKIN 36, GAMMA; IL36G","url":"https://www.omim.org/entry/605542"},{"mim_id":"605510","title":"INTERLEUKIN 37; IL37","url":"https://www.omim.org/entry/605510"},{"mim_id":"605509","title":"INTERLEUKIN 36, ALPHA; IL36A","url":"https://www.omim.org/entry/605509"},{"mim_id":"605507","title":"INTERLEUKIN 36 RECEPTOR ANTAGONIST; IL36RN","url":"https://www.omim.org/entry/605507"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"esophagus","ntpm":385.8},{"tissue":"lymphoid tissue","ntpm":108.2}],"url":"https://www.proteinatlas.org/search/IL36A"},"hgnc":{"alias_symbol":["FIL1","FIL1E","IL-1F6","IL1(EPSILON)","MGC129553","MGC129552"],"prev_symbol":["IL1F6"]},"alphafold":{"accession":"Q9UHA7","domains":[{"cath_id":"2.80.10.50","chopping":"12-55_62-158","consensus_level":"high","plddt":94.5216,"start":12,"end":158}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHA7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHA7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHA7-F1-predicted_aligned_error_v6.png","plddt_mean":92.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL36A","jax_strain_url":"https://www.jax.org/strain/search?query=IL36A"},"sequence":{"accession":"Q9UHA7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UHA7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UHA7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHA7"}},"corpus_meta":[{"pmid":"2953844","id":"PMC_2953844","title":"Human recombinant interleukin 4 induces Fc epsilon receptors (CD23) on normal human B lymphocytes.","date":"1987","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/2953844","citation_count":556,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2965737","id":"PMC_2965737","title":"Human recombinant interleukin 4 induces Fc epsilon R2/CD23 on normal human monocytes.","date":"1988","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/2965737","citation_count":313,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2945890","id":"PMC_2945890","title":"Fc epsilon receptor, a specific differentiation marker transiently expressed on mature B cells before isotype switching.","date":"1986","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/2945890","citation_count":283,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18706831","id":"PMC_18706831","title":"Signalling adaptors used by Toll-like receptors: an update.","date":"2008","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/18706831","citation_count":265,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19506243","id":"PMC_19506243","title":"The cytokine interleukin-33 mediates anaphylactic shock.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19506243","citation_count":227,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11466363","id":"PMC_11466363","title":"Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2.","date":"2001","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11466363","citation_count":213,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12185005","id":"PMC_12185005","title":"Lipopolysaccharide regulates proinflammatory cytokine expression in mouse myoblasts and skeletal muscle.","date":"2002","source":"American journal of physiology. 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2.","date":"2000","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10860666","citation_count":140,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11574262","id":"PMC_11574262","title":"A new nomenclature for IL-1-family genes.","date":"2001","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11574262","citation_count":121,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26813344","id":"PMC_26813344","title":"IL-36α expression is elevated in ulcerative colitis and promotes colonic inflammation.","date":"2016","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26813344","citation_count":118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31736959","id":"PMC_31736959","title":"Biology of IL-36 Signaling and Its Role in Systemic Inflammatory Diseases.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31736959","citation_count":114,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26752465","id":"PMC_26752465","title":"Increased Expression of Interleukin-36, a Member of the Interleukin-1 Cytokine Family, in Inflammatory Bowel Disease.","date":"2016","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/26752465","citation_count":113,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29142248","id":"PMC_29142248","title":"The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29142248","citation_count":104,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16777052","id":"PMC_16777052","title":"Nitroproteins from a human pituitary adenoma tissue discovered with a nitrotyrosine affinity column and tandem mass spectrometry.","date":"2006","source":"Analytical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16777052","citation_count":100,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25902739","id":"PMC_25902739","title":"Interleukin-36α axis is modulated in patients with primary Sjögren's syndrome.","date":"2015","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25902739","citation_count":86,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10512743","id":"PMC_10512743","title":"IL1HY1: A novel interleukin-1 receptor antagonist gene.","date":"1999","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10512743","citation_count":76,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20237496","id":"PMC_20237496","title":"New genetic associations detected in a host response study to hepatitis B vaccine.","date":"2010","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/20237496","citation_count":69,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53010,"output_tokens":902,"usd":0.08628},"stage2":{"model":"claude-opus-4-6","input_tokens":3921,"output_tokens":794,"usd":0.059182},"total_usd":0.437639,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":66840,"output_tokens":4922,"usd":0.137175},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7617,"output_tokens":2610,"usd":0.155002}},"stage1_raw":"Looking through the abstracts, I need to identify papers specifically about IL36A (also known as IL-1 delta, IL-1F6) and extract mechanistic findings. Let me identify the relevant paper.\n\nPaper [6] (PMID: 11466363) is clearly about IL-1 delta (IL36A) and IL-1 epsilon, characterizing them as novel IL-1 family members. This is the key mechanistic paper for IL36A.\n\nAll other papers appear to be about other IL-1 family members (IL-1α, IL-1β, IL-33), IgE receptors (CD23/FcεR), PKC isoforms, or other unrelated topics. None of the other abstracts describe IL36A specifically.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-1 delta (IL36A) was identified as a novel IL-1 family ligand that specifically and potently inhibits IL-1 epsilon (IL36E)-induced NF-κB activation through the orphan receptor IL-1Rrp2 (IL1RL2), functioning as an antagonist of this receptor signaling system. IL-1 epsilon activates NF-κB through IL-1Rrp2, while IL-1 delta inhibits this response, analogous to the IL-1α/β and IL-1 receptor antagonist system.\",\n      \"method\": \"NF-κB-luciferase reporter assays in cells transfected with IL-1Rrp2, with recombinant IL-1 delta and IL-1 epsilon proteins; northern blot and quantitative real-time PCR for expression analysis; keratinocyte stimulation assays\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — functional reporter assay with defined receptor, antagonist activity demonstrated with recombinant proteins, receptor specificity established by testing classical IL-1R pairs\",\n      \"pmids\": [\"11466363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-1 delta (IL36A) and IL-1 epsilon (IL36E) are preferentially expressed in epithelial tissues (skin, lung, stomach), and specifically in keratinocytes but not fibroblasts, endothelial cells, or melanocytes. IL-1 beta/TNF-alpha stimulation of keratinocytes significantly upregulates IL-1 epsilon mRNA expression. In lesional psoriasis skin, mRNA expression of both ligands and their receptor IL-1Rrp2 is increased.\",\n      \"method\": \"Northern blot analysis; quantitative real-time PCR in cell-type-specific cultures; comparison of psoriatic versus normal skin mRNA\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — expression localization by PCR/northern blot with functional context; single lab, single study\",\n      \"pmids\": [\"11466363\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL36A (IL-1 delta) is an IL-1 family cytokine predominantly expressed in epithelial barriers (keratinocytes, skin, lung, stomach) that functions as an antagonist of the IL-1Rrp2 receptor, specifically blocking IL-1 epsilon (IL36E)-induced NF-κB activation, thereby constituting an independent epithelial inflammatory signaling system analogous to IL-1α/β and IL-1 receptor antagonist.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nThe retrieved corpus (97 papers) is almost entirely contaminated — papers about IL-4/IgE/FcεR biology, PKC isoforms, IL-1α/β signaling, IgE receptors, etc. None of these are about the canonical protein IL36A (IL-1F6/IL-36α).\n\nThe gene2pubmed-curated papers (30 papers) contain the relevant ones. Let me identify KEEP papers:\n\n- PMID:11466363 — KEEP (describes IL-1δ/IL-1ε = IL-1F5/IL-1F6 = IL-36Ra/IL-36α; identifies IL-1Rrp2 signaling)\n- PMID:14734551 — KEEP (IL-1F6, IL-1F8, IL-1F9 signal through IL-1Rrp2/IL-1RAcP → NF-κB/MAPKs)\n- PMID:17908936 — KEEP (IL1F6 transgenic mice, IL-1Rrp2/IL-1RAcP-dependent skin inflammation, IL-1F5 antagonism in vivo)\n- PMID:21965679 — KEEP (IL-36α/β/γ processing required for full activity; IL-36Ra mechanism via IL-1Rrp2)\n- PMID:21242515 — KEEP (IL-1F6/IL-1F8/IL-1F9 system in psoriasis, keratinocyte antimicrobial peptide expression)\n- PMID:24829417 — KEEP (IL-36α intradermal injection → chemokines, leukocyte infiltration; monocyte/DC activation via IL-36R)\n- PMID:26813344 — KEEP (IL-36α in ulcerative colitis; IL-36R deficiency reduces disease)\n- PMID:26752465 — KEEP (IL-36α induces CXC chemokines via MyD88/NF-κB/MAPK in intestinal epithelial cells)\n- PMID:29142248 — KEEP (IL-36α activation by neutrophil elastase; cooperation with IL-17A)\n- PMID:23268368 — KEEP (IL-36α in synovium; IL-36α induces IL-6/IL-8 in FLS via p38/NFκB)\n- PMID:10625660 — KEEP (cloning of FIL1ε = IL-1F6 = IL-36α)\n- PMID:10744718 — KEEP (IL-1H1 = IL-36α cloning; induction in keratinocytes by IFN-γ/TNF-α)\n- PMID:10860666 — KEEP (IL-1RP1 cloning = IL-36α)\n- PMID:11991722 — KEEP (genomic map; gene order including IL1F6)\n- PMID:11574262 — KEEP (nomenclature)\n- PMID:11145836 — KEEP (IL-1H characterization - this is IL-1F4/IL-18BP related, not IL-36α — EXCLUDE)\n- PMID:11278614 — KEEP (IL-1HY2 = IL-36β not IL-36α — EXCLUDE)\n- PMID:10512743 — KEEP (IL1HY1 = IL-36Ra antagonist, not IL-36α — EXCLUDE)\n- PMID:8188271 — Genomic map of IL1A/IL1B/IL1RN cluster — EXCLUDE (not about IL36A specifically)\n- PMID:31736959 — KEEP (IL-36 signaling review with mechanistic content about IL-36α)\n- PMID:31486687 — KEEP (GPP/IL-36 pathway)\n- PMID:25902739 — KEEP (IL-36α axis in Sjögren's)\n- PMID:16777052 — KEEP (nitration of IL-1F6/IL-36α detected in pituitary adenoma)\n- PMID:19913121 — EXCLUDE (lipid GWAS, IL1F6 SNP association only)\n- PMID:20237496 — EXCLUDE (vaccine response GWAS)\n- PMID:12477932, 15489334 — EXCLUDE (cDNA library papers)\n- PMID:26186194, 28514442, 33961781 — Interactome MS; these identify IL36A interaction partners — KEEP for binding partners\n- PMID:21873635 — EXCLUDE (GO annotation pipeline)\n\nNow extracting mechanistic discoveries only:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-1F6 (later renamed IL-36α) activates NF-κB signaling through the orphan receptor IL-1Rrp2 (IL-1R-related protein 2), while the closely related IL-1F5 (IL-36Ra) specifically and potently inhibits this IL-1F6/IL-36α response, establishing an independent agonist/antagonist signaling system at IL-1Rrp2.\",\n      \"method\": \"NF-κB–luciferase reporter assays in transfected cell lines; IL-1F5 antagonism of IL-1F6-induced NF-κB activation\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional reporter assay with receptor transfection and antagonist blocking; replicated in subsequent studies\",\n      \"pmids\": [\"11466363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-36α (designated FIL1ε) was cloned as a novel IL-1 family member; protein structure modeling predicts a beta-barrel fold shared with IL-1β/IL-1Ra, and the gene maps to the IL-1 cluster on human chromosome 2q.\",\n      \"method\": \"EST database searches, cDNA cloning, protein structure modeling, chromosomal mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — initial cloning and structural prediction without functional assay\",\n      \"pmids\": [\"10625660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-36α (designated IL-1H1) is constitutively expressed in placenta and squamous epithelium of the esophagus, and can be induced in keratinocytes by IFN-γ and TNF-α in vitro and by contact hypersensitivity or herpes simplex virus infection in vivo, suggesting a role in immune-mediated epithelial responses.\",\n      \"method\": \"Northern blot, in vitro keratinocyte stimulation, in vivo contact hypersensitivity and HSV infection models\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — direct induction experiments in vitro and in vivo, single lab\",\n      \"pmids\": [\"10744718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-36α (IL-1F6), IL-36β (IL-1F8), and IL-36γ (IL-1F9) all signal through both IL-1Rrp2 and IL-1RAcP to activate the NF-κB pathway and MAPKs (JNK and ERK1/2), and downstream targets including an IL-8 promoter and IL-6 secretion. Antibodies to IL-1Rrp2 block signaling, and cytoplasmically-deleted IL-1RAcP acts as a dominant negative, establishing IL-1RAcP as an essential co-receptor.\",\n      \"method\": \"NF-κB reporter assays, receptor transfection, neutralizing antibodies to IL-1Rrp2, dominant-negative IL-1RAcP transfection, MAPK Western blotting, IL-6/IL-8 secretion assays in multiple cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (reporter, dominant-negative, antibody block), multiple cell lines, strong mechanistic conclusions\",\n      \"pmids\": [\"14734551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Transgenic expression of IL-1F6 (IL-36α) in basal keratinocytes in mice caused skin inflammation (acanthosis, hyperkeratosis, mixed inflammatory infiltrate, elevated cytokines/chemokines) in an IL-1Rrp2– and IL-1RAcP–dependent manner. Genetic deletion of IL-1F5 (IL-36Ra) in these mice exacerbated the phenotype, providing in vivo genetic evidence that IL-1F5 is a functional antagonist of IL-1F6/IL-36α.\",\n      \"method\": \"Transgenic mouse generation, genetic epistasis (IL-1F6 transgene × IL-1F5 knockout), histopathology, cytokine/chemokine expression analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic epistasis with receptor-dependence confirmed by double-transgenic/knockout crosses\",\n      \"pmids\": [\"17908936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Full agonist activity of IL-36α (IL-1F6) requires N-terminal truncation to remove a prodomain; truncated IL-36α has ~10³–10⁴-fold greater specific activity (EC₅₀ shifting from ~1 μg/ml to ~1 ng/ml), demonstrating that post-translational proteolytic processing is required for full IL-36α activity.\",\n      \"method\": \"N-terminal truncation series of recombinant proteins, NF-κB reporter assays comparing full-length vs. truncated forms\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic in vitro reconstitution with defined truncation series and quantitative dose-response; replicated across multiple IL-36 family members\",\n      \"pmids\": [\"21965679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-36α (IL-1F6) and related IL-1F cytokines are markedly upregulated in psoriatic skin (2–3 orders of magnitude vs. uninvolved skin), and are induced in normal keratinocytes by IL-1α and TNF-α. IL-36α and IL-1F8 induce expression of antimicrobial peptides (HBD-2, HBD-3, CAMP) and matrix metalloproteinases in reconstituted human epidermis.\",\n      \"method\": \"Quantitative RT-PCR, immunohistochemistry, in vitro keratinocyte stimulation, reconstituted human epidermis model, microarray analysis\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — functional assays in keratinocyte models but primarily correlative in human tissue; mechanistic output (antimicrobial peptide induction) experimentally demonstrated\",\n      \"pmids\": [\"21242515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IL-36α is expressed by CD138+ plasma cells in psoriatic arthritis and rheumatoid arthritis synovium. Recombinant IL-36α activates synovial fibroblasts (FLS) to produce IL-6 and IL-8 through p38 MAPK and NF-κB signaling pathways.\",\n      \"method\": \"Immunohistochemistry, immunofluorescence, Western blot, quantitative RT-PCR, multiplex cytokine assay, immunoblotting for p38/NF-κB activation in FLS\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — receptor-ligand functional assay with signaling pathway validation in primary FLS, single lab\",\n      \"pmids\": [\"23268368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Intradermal injection of IL-36α in mice induces chemokine expression (CXCL1, CXCL8, CCL3, CCL5, CCL20), leukocyte infiltration, and acanthosis. Blood monocytes, myeloid dendritic cells, and monocyte-derived DCs express IL-36R and respond directly to IL-36α by upregulating IL-1β and IL-6 production and DC maturation markers (CD83, CD86, HLA-DR); IL-36α–treated monocyte-derived DCs enhance allogeneic CD4+ T cell proliferation.\",\n      \"method\": \"In vivo intradermal injection, flow cytometry, ELISA, RT-PCR; in vitro monocyte/DC stimulation assays\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro orthogonal approaches defining cellular targets and functional consequences, replicated across multiple cell types\",\n      \"pmids\": [\"24829417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-36α expression is specifically elevated in colonic mucosa of ulcerative colitis patients and in DSS colitis mice. IL-36R-deficient mice exhibit reduced disease severity in DSS colitis with decreased innate inflammatory cell infiltration, and show increased bacterial colonization and altered T helper (enhanced Th17, reduced Th1) responses upon Citrobacter rodentium infection, establishing IL-36R/IL-36α signaling as a mediator of colonic mucosal inflammation and host defense.\",\n      \"method\": \"RT-PCR on patient biopsies, DSS colitis mouse model, Citrobacter rodentium infection model, flow cytometry, IL-36R knockout mice\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function (receptor KO) with defined phenotypic readouts in two independent in vivo disease models\",\n      \"pmids\": [\"26813344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-36α induces expression of CXC chemokines (CXCL1, CXCL2, CXCL3) in intestinal epithelial cells by assembling a MyD88/TRAF6/IRAK1/TAK1 signaling complex that activates NF-κB, AP-1, and MAPK phosphorylation; NF-κB and c-Jun AP-1 siRNA knockdown and MAPK inhibitors reduce IL-36α–induced chemokine expression.\",\n      \"method\": \"ELISA, Western blot, co-immunoprecipitation of signaling complex, siRNA knockdown of NF-κB/AP-1, MAPK inhibitors, RT-PCR in HT-29 cells\",\n      \"journal\": \"Inflammatory bowel diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical complex assembly, genetic (siRNA) and pharmacological inhibition of pathway components, multiple orthogonal approaches\",\n      \"pmids\": [\"26752465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-36γ (and by implication other IL-36 agonists including IL-36α) is secreted from keratinocytes in an inactive form and is proteolytically activated by neutrophil-derived proteases, including neutrophil elastase, which cleaves the N-terminal prodomain to generate the active truncated form. Truncated IL-36 cytokines cooperate synergistically with IL-17A to regulate keratinocyte differentiation and target gene expression.\",\n      \"method\": \"3D organotypic skin models, recombinant protein incubation with purified proteases, N-terminal sequencing, gene expression analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical demonstration of elastase-mediated activation in organotypic model; mechanistic basis for IL-36 processing in vivo\",\n      \"pmids\": [\"29142248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-36α (IL-1 family member 6 / IL-1F6) was identified as a nitroprotein in human pituitary adenoma tissue by nitrotyrosine affinity chromatography and tandem mass spectrometry, demonstrating that IL-36α undergoes tyrosine nitration as a post-translational modification in vivo.\",\n      \"method\": \"Nitrotyrosine affinity column enrichment, trypsin digestion, tandem mass spectrometry\",\n      \"journal\": \"Analytical biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single MS-based detection without functional validation of the nitration\",\n      \"pmids\": [\"16777052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"High-throughput affinity-purification mass spectrometry (BioPlex) identified interaction partners for IL-36α (IL-1F6) in HEK293T cells, placing it within the human interactome network.\",\n      \"method\": \"Affinity-purification mass spectrometry (AP-MS), BioPlex network\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — high-throughput AP-MS without validation of specific IL-36α interactions\",\n      \"pmids\": [\"26186194\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-36α (IL-1F6) is an IL-1 family cytokine that requires N-terminal proteolytic processing (e.g., by neutrophil elastase) for full agonist activity; the processed form signals through a heterodimeric receptor complex of IL-1Rrp2 (IL-1RL2) and IL-1RAcP, recruiting a MyD88/TRAF6/IRAK1/TAK1 signaling complex that activates NF-κB, AP-1, and MAPKs (p38, JNK, ERK1/2) to drive chemokine, IL-6, IL-8, and antimicrobial peptide production, predominantly in epithelial (keratinocyte, intestinal) and myeloid (monocyte, dendritic cell, synovial fibroblast) cell contexts; its activity is antagonized by IL-36Ra (IL-1F5), which binds IL-1Rrp2 and prevents IL-1RAcP co-recruitment.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL36A (IL-1 delta) is an IL-1 family cytokine that functions as a specific antagonist of IL-1Rrp2 (IL1RL2) receptor signaling, blocking IL-1 epsilon (IL-36γ)-induced NF-κB activation in a manner analogous to the IL-1 receptor antagonist opposing IL-1α/β [PMID:11466363]. IL36A is preferentially expressed in epithelial barrier tissues, particularly keratinocytes of the skin, lung, and stomach, and its expression along with that of its cognate ligand and receptor is upregulated in lesional psoriatic skin [PMID:11466363].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"The discovery that IL-1 delta (IL36A) acts as a specific antagonist of IL-1Rrp2 signaling — blocking IL-1 epsilon-induced NF-κB activation — established a second, independent IL-1-like agonist/antagonist signaling axis operating through an orphan receptor in epithelial tissues.\",\n      \"evidence\": \"NF-κB-luciferase reporter assays in IL-1Rrp2-transfected cells with recombinant IL-1 delta and IL-1 epsilon; expression profiling by northern blot and qRT-PCR across tissues and cell types; psoriatic versus normal skin comparison\",\n      \"pmids\": [\"11466363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for antagonism at IL-1Rrp2 is not determined\",\n        \"No in vivo loss-of-function or gain-of-function studies performed\",\n        \"Downstream signaling pathways beyond NF-κB not explored\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The in vivo physiological roles of IL36A in epithelial homeostasis and inflammatory disease, its regulation at the protein level, and whether it engages accessory receptor chains remain uncharacterized in the primary mechanistic literature captured here.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No genetic models or human genetic studies linking IL36A loss to a defined phenotype\",\n        \"Protein-level expression and processing requirements not established\",\n        \"Relationship to IL-36 receptor accessory protein (IL-1RAcP) not defined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IL1RL2\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"IL-36α is a pro-inflammatory IL-1 family cytokine that functions as an agonist of the IL-1Rrp2/IL-1RAcP heterodimeric receptor complex to activate NF-κB, AP-1, and MAPK (p38, JNK, ERK1/2) signaling via a MyD88/TRAF6/IRAK1/TAK1 signaling module, driving production of chemokines (CXCL1, CXCL2, IL-8), IL-6, and antimicrobial peptides in keratinocytes, intestinal epithelial cells, synovial fibroblasts, and myeloid cells [PMID:14734551, PMID:26752465, PMID:24829417]. Full agonist activity requires N-terminal proteolytic removal of a prodomain—achievable by neutrophil elastase—which increases specific activity by 10³–10⁴-fold [PMID:21965679, PMID:29142248]. IL-36α activity is antagonized by IL-36Ra (IL-1F5), which binds IL-1Rrp2 and prevents IL-1RAcP co-recruitment; genetic deletion of IL-36Ra in mice expressing an IL-36α transgene exacerbates skin inflammation [PMID:11466363, PMID:17908936]. IL-36 receptor signaling promotes mucosal inflammation in colitis models and shapes T helper polarization during enteric infection, and IL-36α is markedly upregulated in psoriatic skin and inflamed colonic mucosa [PMID:26813344, PMID:21242515].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of IL-36α as a novel IL-1 family member (FIL1ε/IL-1H1) with a predicted β-barrel fold and gene localization to the IL-1 cluster on chromosome 2q established its molecular identity, while initial expression profiling revealed constitutive expression in squamous epithelium and inducibility by IFN-γ and TNF-α in keratinocytes.\",\n      \"evidence\": \"cDNA cloning, structural modeling, Northern blot, keratinocyte stimulation, and in vivo contact-hypersensitivity/HSV models\",\n      \"pmids\": [\"10625660\", \"10744718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor identified at this stage\", \"No functional activity assay performed\", \"Protein processing requirements unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The first functional assay demonstrated that IL-36α activates NF-κB through the orphan receptor IL-1Rrp2 and that IL-36Ra (IL-1F5) specifically blocks this activation, establishing an agonist–antagonist signaling axis distinct from classical IL-1.\",\n      \"evidence\": \"NF-κB luciferase reporter assays with IL-1Rrp2 transfection and IL-1F5 antagonism\",\n      \"pmids\": [\"11466363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of co-receptor (IL-1RAcP) not yet established\", \"Downstream signaling cascades beyond NF-κB unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"IL-1RAcP was identified as an essential co-receptor: dominant-negative IL-1RAcP and neutralizing anti-IL-1Rrp2 antibodies blocked IL-36α signaling, and JNK/ERK1/2 MAPK cascades were identified as additional downstream effectors alongside NF-κB, with IL-6 and IL-8 as functional outputs.\",\n      \"evidence\": \"Receptor transfection, dominant-negative IL-1RAcP, neutralizing antibodies, MAPK Western blotting, IL-6/IL-8 secretion assays in multiple cell lines\",\n      \"pmids\": [\"14734551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for IL-1Rrp2/IL-1RAcP heterodimerization not resolved\", \"Requirement for N-terminal processing not yet recognized\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"In vivo genetic evidence confirmed the agonist–antagonist paradigm: transgenic IL-36α expression in mouse basal keratinocytes caused IL-1Rrp2/IL-1RAcP-dependent skin inflammation, and concurrent IL-36Ra knockout exacerbated the phenotype, proving IL-36Ra is a physiological antagonist in vivo.\",\n      \"evidence\": \"Transgenic/knockout mouse crosses with histopathology and cytokine expression analysis\",\n      \"pmids\": [\"17908936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous protease responsible for IL-36α activation in skin not identified\", \"Relative contribution of IL-36α vs. other IL-36 agonists in skin inflammation unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Two key advances clarified IL-36α biology: systematic N-terminal truncation showed that prodomain removal increases specific activity by 10³–10⁴-fold, explaining previously discrepant dose–response data; and IL-36α was found massively upregulated in psoriatic skin where it induces antimicrobial peptides (HBD-2, HBD-3, CAMP) in reconstituted human epidermis.\",\n      \"evidence\": \"Recombinant truncation series with quantitative NF-κB reporter dose–response; qRT-PCR on patient biopsies; reconstituted human epidermis stimulation\",\n      \"pmids\": [\"21965679\", \"21242515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo protease responsible for N-terminal processing not yet identified\", \"Role in psoriasis causation vs. consequence not formally tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Cellular target breadth was expanded beyond epithelia: monocytes, myeloid DCs, and monocyte-derived DCs were shown to express IL-36R and respond to IL-36α by producing IL-1β and IL-6 and upregulating maturation markers; IL-36α-treated DCs enhanced CD4+ T cell proliferation, establishing a link between IL-36α and adaptive immune priming.\",\n      \"evidence\": \"In vivo intradermal injection, flow cytometry, ELISA, in vitro monocyte/DC stimulation, allogeneic T cell proliferation assays\",\n      \"pmids\": [\"24829417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IL-36α acts directly on T cells not resolved\", \"Relative potency of IL-36α vs. IL-36β/γ on myeloid cells not compared\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Two studies established IL-36α function in the intestinal compartment: IL-36R-deficient mice showed reduced DSS colitis severity and altered T helper polarization (enhanced Th17, reduced Th1) during Citrobacter rodentium infection; mechanistically, IL-36α assembles a MyD88/TRAF6/IRAK1/TAK1 complex in intestinal epithelial cells to activate NF-κB, AP-1, and MAPKs for CXC chemokine production.\",\n      \"evidence\": \"IL-36R knockout mice in DSS colitis and enteric infection models; co-immunoprecipitation of signaling complex, siRNA and pharmacological pathway inhibition in HT-29 cells\",\n      \"pmids\": [\"26813344\", \"26752465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific IL-36α protease in the intestinal milieu not identified\", \"Whether IL-36α signals in intestinal immune cells independently of epithelial chemokine induction not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Neutrophil elastase was identified as a physiologically relevant protease that cleaves the IL-36 prodomain to generate active cytokine, and truncated IL-36 cytokines were shown to synergize with IL-17A in regulating keratinocyte differentiation, connecting neutrophil recruitment to amplification of IL-36 signaling.\",\n      \"evidence\": \"3D organotypic skin models, incubation with purified neutrophil elastase, N-terminal sequencing, gene expression analysis\",\n      \"pmids\": [\"29142248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether elastase is the predominant processing protease in vivo or if other proteases contribute\", \"Structural basis of IL-36/IL-17A synergistic signaling not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of the IL-36α/IL-1Rrp2/IL-1RAcP ternary complex, the full repertoire of activating proteases across tissues, direct effects on lymphocyte subsets, and whether IL-36α has non-redundant functions relative to IL-36β and IL-36γ.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of IL-36α/receptor complex\", \"Non-redundancy among IL-36 agonists not tested by individual genetic deletion\", \"Intracellular vs. extracellular processing compartment undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 3, 5, 8, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5, 8, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 4, 8, 9, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IL1RL2\",\n      \"IL1RAP\",\n      \"MYD88\",\n      \"TRAF6\",\n      \"IRAK1\",\n      \"MAP3K7\",\n      \"IL36RN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}