{"gene":"IL36RN","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":1999,"finding":"IL36RN (then called IL1HY1) was identified as a novel member of the IL-1 receptor antagonist gene family, encoding a protein with 52% amino acid homology to IL-1Ra, mapped to chromosome 2q near the IL-1 locus, and shown to be predominantly expressed in skin with inducibility in THP-1 cells by PMA and LPS treatment.","method":"cDNA cloning, chromosomal mapping, Northern blot expression analysis, EST database searching","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — foundational cloning and expression characterization, single lab with multiple methods","pmids":["10512743"],"is_preprint":false},{"year":2000,"finding":"IL36RN (IL-1RP3/IL-1F5) was identified as one of three novel IL-1 family members within the IL-1 gene cluster on chromosome 2q, sharing a signature IL-1 family motif, more closely related to IL-1Ra, lacking a conventional hydrophobic signal sequence, and showing highly restricted expression in epithelial cell populations.","method":"EST database searching, genomic sequencing, sequence homology analysis, expression analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — genomic and expression characterization, multiple methods, replicated by concurrent publications","pmids":["10860666"],"is_preprint":false},{"year":2000,"finding":"The IL36RN (IL1HY1) gene was found to contain four coding exons, with the 5' UTR formed by alternatively used exons, and intron positions within the protein-coding region are conserved with IL-1Ra, providing evidence that IL36RN and IL-1Ra arose from duplication of a primordial IL-1 receptor antagonist gene.","method":"Genomic sequencing (~7,600 nucleotides), exon-intron structure determination, comparative genomics","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 2 — complete gene structure determination with evolutionary inference, single lab","pmids":["10866108"],"is_preprint":false},{"year":2000,"finding":"IL36RN (FIL1delta/IL-1F5) was cloned and characterized as an IL-1 family member with structural homology to IL-1Ra by protein structure modeling, placed in a gene cluster on chromosome 2q with conserved exon-intron arrangement shared with other IL-1 family members.","method":"cDNA cloning, protein structure modeling, chromosomal mapping, sequence analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — structural modeling plus genomic characterization, replicated by concurrent publications","pmids":["10625660"],"is_preprint":false},{"year":2000,"finding":"IL36RN (IL-1H1) was shown by circular dichroism spectra and thermal stability analysis to fold similarly to IL-1Ra, is constitutively expressed only in placenta and squamous epithelium of the esophagus, and can be induced in keratinocytes by interferon-gamma and TNF-alpha and in vivo via contact hypersensitivity or herpes simplex virus infection.","method":"Circular dichroism spectroscopy, thermal stability analysis, expression cloning, in vivo induction models","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1/2 — biophysical (CD spectroscopy) demonstration of IL-1Ra-like fold, multiple methods, single lab","pmids":["10744718"],"is_preprint":false},{"year":2001,"finding":"IL36RN (IL-1delta) was demonstrated to function as a specific and potent antagonist of IL-1epsilon (IL-36γ)-mediated NF-κB activation through the orphan receptor IL-1Rrp2 (IL-36R), establishing that IL-1delta/IL36RN, IL-1epsilon, and IL-1Rrp2 constitute an independent signaling system analogous to IL-1αβ/IL-1Ra/IL-1R1.","method":"NF-κB-luciferase reporter assay, receptor specificity assays, quantitative real-time PCR","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1/2 — functional reporter assay directly demonstrating antagonism mechanism, multiple orthogonal methods, replicated in subsequent work","pmids":["11466363"],"is_preprint":false},{"year":2002,"finding":"Precise chromosomal mapping of the IL-1 gene cluster established that IL36RN (IL1F5) is located on chromosome 2q between IL1F8 and IL1F10, with gene order from centromere to telomere being IL1A-IL1B-IL1F7-IL1F9-IL1F6-IL1F8-IL1F5-IL1F10-IL1RN, and that key features of exon boundaries are conserved across family members.","method":"Genomic sequencing, physical mapping, SNP and microsatellite marker mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — comprehensive sequence-based mapping, single consortium effort with multiple methods","pmids":["11991722"],"is_preprint":false},{"year":2011,"finding":"IL36RN (IL-1F5) antagonist activity requires N-terminal processing: removal of the N-terminal methionine to yield Val-2 as the start residue is required for full antagonist activity. Val-2-initiated IL-36Ra fully inhibits IL-36α, IL-36β, and IL-36γ. The mechanism of IL-36Ra antagonism is analogous to IL-1Ra: IL-36Ra binds to IL-1Rrp2 (IL-36R) and prevents IL-1RAcP recruitment, thereby blocking formation of a functional signaling complex.","method":"In vitro antagonist activity assays with N-terminally truncated recombinant proteins, chimeric receptor experiments, co-immunoprecipitation, cell-based signaling assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with mutagenesis, co-IP, chimeric receptor epistasis; multiple orthogonal methods in single study","pmids":["21965679"],"is_preprint":false},{"year":2011,"finding":"IL36RN (IL-1F5/IL-36Ra) expression is increased 2–3 orders of magnitude in psoriasis plaque skin versus uninvolved skin. IL-36Ra (IL-1F5) is induced in normal keratinocytes by IL-1α and TNF-α, and its expression decreases with etanercept treatment concomitant with clinical improvement, placing it as part of the IL-1F5/F6/F8/F9 signaling system active in inflammatory skin disease.","method":"Quantitative RT-PCR, immunohistochemistry, mouse models of psoriasis, microarray analysis of reconstituted human epidermis","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2/3 — multiple expression methods plus functional microarray in tissue model, single lab","pmids":["21242515"],"is_preprint":false},{"year":2011,"finding":"Loss-of-function mutations in IL36RN (p.Ser113Leu and p.Arg48Trp, altering evolutionarily conserved residues) cause generalized pustular psoriasis (GPP). Homozygosity for the p.Ser113Leu variant is associated with an elevated proinflammatory cytokine response following ex vivo stimulation with IL-36α, demonstrating that IL36RN loss of function leads to unopposed IL-36 signaling and systemic inflammation.","method":"Exome sequencing, Sanger validation, population genetics, ex vivo cytokine stimulation assay","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — exome sequencing combined with functional ex vivo assay demonstrating elevated proinflammatory response upon IL36RN loss, replicated across multiple subsequent studies","pmids":["21839423"],"is_preprint":false},{"year":2012,"finding":"IL-36Ra (IL36RN protein) binds specifically to the IL-36 receptor (IL-1Rrp2) as demonstrated by screening immobilized extracellular domains of all IL-1 receptor family members, and has biological effects on immune cells (inhibiting IL-22 and IL-17 production from T lymphocytes and IL-8 from monocytes stimulated with IL-36γ) similar to those of IL-38 acting via the same receptor.","method":"Receptor-binding screen with immobilized extracellular domains of IL-1 receptor family members, PBMC cytokine production assays, dendritic cell activation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1/2 — direct receptor-binding screen across all IL-1R family members plus multiple functional assays in primary human cells","pmids":["22315422"],"is_preprint":false},{"year":2013,"finding":"Homozygous or compound heterozygous IL36RN mutations account for the majority (9 of 11 cases) of GPP without psoriasis vulgaris in a Japanese cohort, establishing that GPP-alone is a distinct disease subtype caused by deficiency of IL-36 receptor antagonist, while GPP with psoriasis vulgaris has a different genetic etiology.","method":"IL36RN mutation screening by sequencing, genotype-phenotype correlation analysis","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 3 — genetic screening study with strong genotype-phenotype correlation but no direct functional assay of mutant proteins","pmids":["23698098"],"is_preprint":false},{"year":2013,"finding":"Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes beyond GPP, including palmoplantar pustulosis and acrodermatitis continua of Hallopeau, extending the loss-of-function disease spectrum of IL36RN.","method":"Candidate gene sequencing, genotype-phenotype correlation","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 3 — genetic variant identification with phenotypic correlation, no in vitro functional assay of mutants","pmids":["23303454"],"is_preprint":false},{"year":2013,"finding":"Rare variations in IL36RN are found in patients with acute generalized exanthematous pustulosis (AGEP), a severe adverse drug reaction, suggesting that reduced IL-36 receptor antagonist function is a predisposing factor for this drug-induced pustular phenotype.","method":"Candidate gene sequencing in AGEP cases versus controls","journal":"The Journal of investigative dermatology","confidence":"Low","confidence_rationale":"Tier 3 — genetic association with no functional validation of variants in pustular drug reaction context","pmids":["23358093"],"is_preprint":false},{"year":2014,"finding":"IL-36Ra (IL36RN protein), produced by keratinocytes, acts to limit IL-36-driven skin inflammation: in the absence of adequate IL-36Ra, IL-36 cytokines drive expression of chemokines (CXCL1, CXCL8, CCL3, CCL5, CCL20) in keratinocytes and activate myeloid dendritic cells and monocytes via IL-36R, promoting myeloid cell infiltration and acanthosis.","method":"Human keratinocyte cytokine treatment, intradermal injection of IL-36α in mice, flow cytometry, ELISA, allogeneic T cell proliferation assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple in vitro and in vivo methods demonstrating IL-36Ra-opposed pathway, single lab","pmids":["24829417"],"is_preprint":false},{"year":2014,"finding":"IL36RN mutations (including p.Ser113Leu) define a severe autoinflammatory phenotype of GPP with systemic features, and some patients with IL36RN deficiency respond poorly to conventional psoriasis treatments but may benefit from IL-1 pathway blockade, further validating IL36RN loss-of-function as mechanistically driving IL-36 pathway overactivation.","method":"IL36RN sequencing, clinical phenotyping, treatment response analysis","journal":"The Journal of allergy and clinical immunology","confidence":"Low","confidence_rationale":"Tier 3 — clinical genotype-phenotype study, limited direct mechanistic experimentation","pmids":["25458002"],"is_preprint":false}],"current_model":"IL36RN encodes IL-36Ra, a secreted IL-1 family receptor antagonist that, following N-terminal processing (removal of the initiator methionine to expose Val-2), binds specifically to the IL-36 receptor (IL-1Rrp2/IL-1RL2) and blocks recruitment of the co-receptor IL-1RAcP, thereby preventing assembly of a functional signaling complex and opposing the pro-inflammatory activities of IL-36α, IL-36β, and IL-36γ; loss-of-function mutations in IL36RN result in unopposed IL-36 signaling in keratinocytes and myeloid cells, manifesting clinically as generalized pustular psoriasis and related pustular inflammatory diseases."},"narrative":{"teleology":[{"year":1999,"claim":"Identification of IL36RN as a novel IL-1 receptor antagonist family member established that a second receptor antagonist gene existed within the IL-1 locus, raising the question of which receptor system it controlled.","evidence":"cDNA cloning, chromosomal mapping, Northern blot in skin and THP-1 cells","pmids":["10512743"],"confidence":"Medium","gaps":["Target receptor unknown","No demonstration of antagonist activity","Processing and activation requirements uncharacterized"]},{"year":2000,"claim":"Concurrent genomic, structural, and expression studies from multiple groups confirmed IL36RN as a bona fide IL-1 family member with an IL-1Ra-like fold, conserved exon-intron structure indicating gene duplication origin, and highly restricted epithelial expression, resolving its evolutionary relationship but not its function.","evidence":"Genomic sequencing, circular dichroism spectroscopy, protein structure modeling, expression profiling across tissues","pmids":["10860666","10866108","10625660","10744718"],"confidence":"Medium","gaps":["Functional antagonism not yet demonstrated in any assay","Cognate receptor and agonists not identified","Biological role in skin immunity not established"]},{"year":2001,"claim":"Reporter assays demonstrated that IL-36Ra specifically antagonizes IL-36γ-mediated NF-κB activation through IL-1Rrp2, establishing IL-36Ra/IL-36γ/IL-1Rrp2 as an independent IL-1 family signaling axis analogous to IL-1Ra/IL-1/IL-1R1.","evidence":"NF-κB-luciferase reporter assay with receptor specificity panels, quantitative RT-PCR","pmids":["11466363"],"confidence":"High","gaps":["Mechanism of antagonism (co-receptor blockade vs. competitive displacement) not resolved","N-terminal processing requirements unknown","Antagonism of IL-36α and IL-36β not tested"]},{"year":2011,"claim":"Biochemical reconstitution showed that IL-36Ra requires N-terminal methionine removal to achieve full antagonist potency and that it blocks signaling by preventing IL-1RAcP recruitment to the IL-36R, resolving the molecular mechanism of antagonism and extending it to all three IL-36 agonists.","evidence":"Truncation mutagenesis of recombinant proteins, chimeric receptor experiments, co-immunoprecipitation, cell-based signaling assays","pmids":["21965679"],"confidence":"High","gaps":["Protease responsible for N-terminal processing in vivo not identified","Structural basis of receptor binding at atomic resolution not determined","Stoichiometry and kinetics of receptor complex blockade not measured"]},{"year":2011,"claim":"Two discoveries converged to establish IL36RN in human disease: expression profiling showed massive IL-36Ra upregulation in psoriatic skin, while exome sequencing identified homozygous loss-of-function mutations (p.Ser113Leu, p.Arg48Trp) as the cause of generalized pustular psoriasis, with ex vivo demonstration of unopposed IL-36 signaling in mutation carriers.","evidence":"qRT-PCR and immunohistochemistry in psoriatic lesions; exome sequencing with Sanger validation and ex vivo cytokine stimulation assay in patient PBMCs","pmids":["21242515","21839423"],"confidence":"High","gaps":["Structural impact of individual missense mutations not resolved","Whether partial loss-of-function alleles contribute to common psoriasis unknown","Cell-type-specific contribution (keratinocyte vs. myeloid) to disease pathogenesis not delineated"]},{"year":2012,"claim":"A systematic receptor-binding screen across all IL-1 receptor family members confirmed exclusive IL-36Ra binding to IL-1Rrp2 and demonstrated functional suppression of IL-22, IL-17, and IL-8 production from primary human immune cells, establishing physiological anti-inflammatory effects beyond keratinocytes.","evidence":"Immobilized extracellular domain binding screen, PBMC and dendritic cell cytokine assays","pmids":["22315422"],"confidence":"High","gaps":["Relative contribution of IL-36Ra vs. IL-38 at the same receptor not resolved","In vivo immune cell targets in human tissue not mapped","Binding affinity and receptor occupancy not quantified"]},{"year":2013,"claim":"Expanded genetic studies established that IL36RN mutations account for the majority of GPP-without-psoriasis-vulgaris cases and that the disease spectrum extends to palmoplantar pustulosis and acrodermatitis continua of Hallopeau, defining DITRA as a distinct autoinflammatory entity.","evidence":"IL36RN mutation screening by sequencing in Japanese and European cohorts, genotype-phenotype correlation","pmids":["23698098","23303454"],"confidence":"Medium","gaps":["No in vitro functional assessment of most identified mutant proteins","Genetic modifiers and incomplete penetrance factors uncharacterized","Whether heterozygous carriers have subclinical phenotype not established"]},{"year":2014,"claim":"Functional studies in keratinocytes and mouse models defined the downstream effector pathway: in the absence of IL-36Ra, IL-36 agonists drive expression of neutrophil-attracting chemokines (CXCL1, CXCL8, CCL20) and activate myeloid dendritic cells, explaining the neutrophilic pustular pathology of DITRA.","evidence":"Keratinocyte cytokine treatment, intradermal IL-36α injection in mice, flow cytometry, ELISA","pmids":["24829417"],"confidence":"Medium","gaps":["Contribution of adaptive immunity and specific T cell subsets downstream of IL-36 not defined","Whether IL-36Ra directly modulates neutrophil function unknown","Tissue-specific regulatory mechanisms controlling IL-36Ra expression not identified"]},{"year":null,"claim":"Key unresolved questions include the identity of the protease(s) that process IL-36Ra N-terminally in vivo, the atomic-resolution structure of the IL-36Ra–IL-36R complex, and the mechanistic basis by which specific IL36RN missense mutations differentially affect protein stability versus receptor binding.","evidence":"","pmids":[],"confidence":"High","gaps":["In vivo processing protease not identified","No crystal or cryo-EM structure of IL-36Ra bound to IL-36R","Structure-function relationship of disease-causing missense mutations not systematically characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,7,10]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[5,7,10]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,4,10]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,7,10,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,11,12]}],"complexes":[],"partners":["IL1RL2","IL1RAP"],"other_free_text":[]},"mechanistic_narrative":"IL36RN encodes interleukin-36 receptor antagonist (IL-36Ra), a secreted IL-1 family member that functions as a specific antagonist of the IL-36 signaling axis by binding the IL-36 receptor (IL-1Rrp2/IL-1RL2) and preventing recruitment of the co-receptor IL-1RAcP, thereby blocking NF-κB activation driven by IL-36α, IL-36β, and IL-36γ [PMID:11466363, PMID:21965679, PMID:22315422]. Full antagonist activity requires N-terminal processing—removal of the initiator methionine to expose Val-2—and the mature protein adopts an IL-1Ra-like β-trefoil fold, consistent with its origin by duplication of a primordial IL-1 receptor antagonist gene [PMID:21965679, PMID:10744718, PMID:10866108]. IL-36Ra is predominantly expressed in keratinocytes and squamous epithelia, is induced by pro-inflammatory stimuli (IL-1α, TNF-α, IFN-γ), and limits IL-36-driven chemokine production and myeloid cell recruitment in the skin [PMID:10744718, PMID:21242515, PMID:24829417]. Loss-of-function mutations in IL36RN cause deficiency of IL-36 receptor antagonist (DITRA), manifesting as generalized pustular psoriasis and related pustular inflammatory phenotypes due to unopposed IL-36 signaling [PMID:21839423, PMID:23698098]."},"prefetch_data":{"uniprot":{"accession":"Q9UBH0","full_name":"Interleukin-36 receptor antagonist protein","aliases":["FIL1 delta","IL-1-related protein 3","IL-1RP3","Interleukin-1 HY1","IL-1HY1","Interleukin-1 delta","IL-1 delta","Interleukin-1 family member 5","IL-1F5","Interleukin-1 receptor antagonist homolog 1","IL-1ra homolog 1","Interleukin-1-like protein 1","IL-1L1"],"length_aa":155,"mass_kda":17.0,"function":"Inhibits the activity of interleukin-36 (IL36A,IL36B and IL36G) by binding to receptor IL1RL2 and preventing its association with the coreceptor IL1RAP for signaling. 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. Proposed to play a role in skin inflammation. May be involved in the innate immune response to fungal pathogens, such as Aspergillus fumigatus. May activate an anti-inflammatory signaling pathway by recruiting SIGIRR","subcellular_location":"Cytoplasm; Secreted","url":"https://www.uniprot.org/uniprotkb/Q9UBH0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL36RN","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/IL36RN","total_profiled":1310},"omim":[{"mim_id":"616106","title":"PSORIASIS 15, PUSTULAR, SUSCEPTIBILITY TO; PSORS15","url":"https://www.omim.org/entry/616106"},{"mim_id":"615781","title":"ADAPTOR-RELATED PROTEIN COMPLEX 1, SIGMA-3 SUBUNIT; AP1S3","url":"https://www.omim.org/entry/615781"},{"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":"607211","title":"CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 14; CARD14","url":"https://www.omim.org/entry/607211"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"esophagus","ntpm":26.1},{"tissue":"lymphoid tissue","ntpm":42.2},{"tissue":"skin 1","ntpm":60.0}],"url":"https://www.proteinatlas.org/search/IL36RN"},"hgnc":{"alias_symbol":["FIL1","FIL1(DELTA)","FIL1D","IL1HY1","IL1RP3","IL1L1","IL-1F5","IL36RA","MGC29840"],"prev_symbol":["IL1F5"]},"alphafold":{"accession":"Q9UBH0","domains":[{"cath_id":"2.80.10.50","chopping":"8-150","consensus_level":"high","plddt":93.7991,"start":8,"end":150}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBH0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBH0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBH0-F1-predicted_aligned_error_v6.png","plddt_mean":92.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL36RN","jax_strain_url":"https://www.jax.org/strain/search?query=IL36RN"},"sequence":{"accession":"Q9UBH0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UBH0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UBH0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBH0"}},"corpus_meta":[{"pmid":"10860666","id":"PMC_10860666","title":"Identification 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expression.","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21242515","citation_count":254,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24829417","id":"PMC_24829417","title":"IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24829417","citation_count":253,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23698098","id":"PMC_23698098","title":"The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist.","date":"2013","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/23698098","citation_count":249,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15231748","id":"PMC_15231748","title":"Functional proteomics mapping of a human signaling pathway.","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15231748","citation_count":247,"is_preprint":false,"source_track":"gene2pubmed"},{"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":"gene2pubmed"},{"pmid":"11145836","id":"PMC_11145836","title":"IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp.","date":"2001","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/11145836","citation_count":169,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11278614","id":"PMC_11278614","title":"Cloning and characterization of IL-1HY2, a novel interleukin-1 family member.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11278614","citation_count":169,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11991722","id":"PMC_11991722","title":"A sequence-based map of the nine genes of the human interleukin-1 cluster.","date":"2002","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11991722","citation_count":168,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19913121","id":"PMC_19913121","title":"Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.","date":"2009","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19913121","citation_count":164,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17975119","id":"PMC_17975119","title":"Association of gene variants with incident myocardial infarction in the Cardiovascular Health Study.","date":"2007","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17975119","citation_count":142,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23303454","id":"PMC_23303454","title":"Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes.","date":"2013","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/23303454","citation_count":137,"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":"25458002","id":"PMC_25458002","title":"IL36RN mutations define a severe autoinflammatory phenotype of generalized pustular psoriasis.","date":"2014","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25458002","citation_count":115,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23358093","id":"PMC_23358093","title":"Rare variations in IL36RN in severe adverse drug reactions manifesting as acute generalized exanthematous pustulosis.","date":"2013","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/23358093","citation_count":112,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3155,"output_tokens":787,"usd":0.010635},"stage2":{"model":"claude-opus-4-6","input_tokens":3970,"output_tokens":921,"usd":0.064312},"total_usd":0.287841,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of 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and characterization with multiple methods but no functional reconstitution of antagonist activity\",\n      \"pmids\": [\"10512743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL36RN (IL1HY1) gene structure was determined to contain four coding exons; the 5' UTR is formed by alternatively used exons, and intron positions are conserved with IL-1ra, indicating these genes arose from duplication of a primordial IL-1 receptor antagonist gene. Like intracellular IL-1Ra, IL36RN lacks a conventional hydrophobic signal sequence.\",\n      \"method\": \"Genomic sequencing (~7,600 nucleotides), exon-intron boundary mapping, comparative gene structure analysis\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic sequencing with comparative structural analysis, single lab\",\n      \"pmids\": [\"10866108\", \"10860666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL36RN (IL-1RP) expression is highly restricted to epithelial cell populations, consistent with its role in epithelial inflammatory responses, and the protein belongs to a subgroup more closely related to IL-1Ra within the IL-1 family cluster on chromosome 2q.\",\n      \"method\": \"EST database mining, genomic sequencing of chromosome 2q, expression profiling across tissue types\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — identification by genomic sequencing and expression analysis across multiple tissues, replicated across two independent groups\",\n      \"pmids\": [\"10860666\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL36RN encodes a secreted (though lacking a classical signal sequence) IL-1 receptor antagonist-like protein restricted primarily to epithelial cells, structurally homologous to IL-1Ra (52% identity), residing in the IL-1 gene cluster on chromosome 2q, with expression inducible by pro-inflammatory stimuli (LPS, PMA), and gene structure conserved with IL-1Ra suggesting it acts as an antagonist of IL-36 receptor signaling in epithelial inflammatory contexts.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries from KEPT papers.\n\n**Classification:**\n\n- [1] PMID:10860666 — KEEP (describes IL-1RP family including IL-1F5/IL36RN, foundational genomic characterization)\n- [2] PMID:10512743 — KEEP (IL1HY1 = IL36RN, foundational characterization)\n- [3] PMID:10866108 — KEEP (IL1HY1 = IL36RN gene organization)\n- [4] bio_10.1101_2025.02.25.640192 — EXCLUDE (IL36RN mentioned only as a downstream regulated gene in TSLP signaling study; no mechanistic findings about IL36RN itself)\n- PMID:16189514 — EXCLUDE (proteome-scale interactome map; IL36RN appears incidentally)\n- PMID:12477932 — EXCLUDE (cDNA sequencing project; no IL36RN-specific mechanism)\n- PMID:28514442 — EXCLUDE (proteome-scale interactome; no IL36RN-specific mechanism)\n- PMID:25416956 — EXCLUDE (interactome map; no IL36RN-specific mechanism)\n- PMID:32296183 — EXCLUDE (interactome map; no IL36RN-specific mechanism)\n- PMID:14702039 — EXCLUDE (cDNA sequencing; no IL36RN-specific mechanism)\n- PMID:21839423 — KEEP (IL36RN mutations, loss-of-function, functional ex vivo assay)\n- PMID:22315422 — KEEP (IL-36Ra receptor binding, functional characterization)\n- PMID:12975309 — EXCLUDE (SPDI; no IL36RN-specific mechanism)\n- PMID:21965679 — KEEP (mechanistic study of IL-36Ra processing and antagonism)\n- PMID:8188271 — EXCLUDE (physical map of IL-1 region; no IL36RN-specific mechanism)\n- PMID:10625660 — KEEP (cloning/characterization of IL-1 family including IL-1F5/IL36RN)\n- PMID:10744718 — KEEP (characterization of IL-1H1 = IL36RN; biochemical folding data)\n- PMID:21242515 — KEEP (IL-1F5/IL36RN expression and signaling in skin)\n- PMID:24829417 — KEEP (IL-36Ra function in skin immune system)\n- PMID:23698098 — KEEP (IL36RN loss-of-function in GPP)\n- PMID:15231748 — EXCLUDE (Smad signaling; no IL36RN mechanism)\n- PMID:11466363 — KEEP (IL-1delta = IL36RN, NF-κB antagonism via IL-1Rrp2)\n- PMID:11145836 — EXCLUDE (IL-1H binds IL-18R, not IL36RN)\n- PMID:11278614 — EXCLUDE (IL-1HY2 is a different family member)\n- PMID:11991722 — KEEP (gene cluster map, structural/genomic characterization of IL1F5)\n- PMID:19913121 — EXCLUDE (lipid/CVD GWAS; no IL36RN mechanism)\n- PMID:17975119 — EXCLUDE (CVD SNP study; no IL36RN mechanism)\n- PMID:23303454 — KEEP (IL36RN rare variants, pustular phenotypes)\n- PMID:11574262 — KEEP (nomenclature; establishes IL1F5 = IL36RN identity)\n- PMID:25458002 — KEEP (IL36RN mutations, autoinflammatory phenotype)\n- PMID:23358093 — KEEP (IL36RN rare variants in AGEP)\n- PMID:21873635 — EXCLUDE (GO annotation methods; no IL36RN mechanism)\n- PMID:15489334 — EXCLUDE (MGC cDNA project; no IL36RN mechanism)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"IL36RN (then called IL1HY1) was identified as a novel member of the IL-1 receptor antagonist gene family, encoding a protein with 52% amino acid homology to IL-1Ra, mapped to chromosome 2q near the IL-1 locus, and shown to be predominantly expressed in skin with inducibility in THP-1 cells by PMA and LPS treatment.\",\n      \"method\": \"cDNA cloning, chromosomal mapping, Northern blot expression analysis, EST database searching\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — foundational cloning and expression characterization, single lab with multiple methods\",\n      \"pmids\": [\"10512743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL36RN (IL-1RP3/IL-1F5) was identified as one of three novel IL-1 family members within the IL-1 gene cluster on chromosome 2q, sharing a signature IL-1 family motif, more closely related to IL-1Ra, lacking a conventional hydrophobic signal sequence, and showing highly restricted expression in epithelial cell populations.\",\n      \"method\": \"EST database searching, genomic sequencing, sequence homology analysis, expression analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genomic and expression characterization, multiple methods, replicated by concurrent publications\",\n      \"pmids\": [\"10860666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The IL36RN (IL1HY1) gene was found to contain four coding exons, with the 5' UTR formed by alternatively used exons, and intron positions within the protein-coding region are conserved with IL-1Ra, providing evidence that IL36RN and IL-1Ra arose from duplication of a primordial IL-1 receptor antagonist gene.\",\n      \"method\": \"Genomic sequencing (~7,600 nucleotides), exon-intron structure determination, comparative genomics\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — complete gene structure determination with evolutionary inference, single lab\",\n      \"pmids\": [\"10866108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL36RN (FIL1delta/IL-1F5) was cloned and characterized as an IL-1 family member with structural homology to IL-1Ra by protein structure modeling, placed in a gene cluster on chromosome 2q with conserved exon-intron arrangement shared with other IL-1 family members.\",\n      \"method\": \"cDNA cloning, protein structure modeling, chromosomal mapping, sequence analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — structural modeling plus genomic characterization, replicated by concurrent publications\",\n      \"pmids\": [\"10625660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL36RN (IL-1H1) was shown by circular dichroism spectra and thermal stability analysis to fold similarly to IL-1Ra, is constitutively expressed only in placenta and squamous epithelium of the esophagus, and can be induced in keratinocytes by interferon-gamma and TNF-alpha and in vivo via contact hypersensitivity or herpes simplex virus infection.\",\n      \"method\": \"Circular dichroism spectroscopy, thermal stability analysis, expression cloning, in vivo induction models\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — biophysical (CD spectroscopy) demonstration of IL-1Ra-like fold, multiple methods, single lab\",\n      \"pmids\": [\"10744718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IL36RN (IL-1delta) was demonstrated to function as a specific and potent antagonist of IL-1epsilon (IL-36γ)-mediated NF-κB activation through the orphan receptor IL-1Rrp2 (IL-36R), establishing that IL-1delta/IL36RN, IL-1epsilon, and IL-1Rrp2 constitute an independent signaling system analogous to IL-1αβ/IL-1Ra/IL-1R1.\",\n      \"method\": \"NF-κB-luciferase reporter assay, receptor specificity assays, quantitative real-time PCR\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — functional reporter assay directly demonstrating antagonism mechanism, multiple orthogonal methods, replicated in subsequent work\",\n      \"pmids\": [\"11466363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Precise chromosomal mapping of the IL-1 gene cluster established that IL36RN (IL1F5) is located on chromosome 2q between IL1F8 and IL1F10, with gene order from centromere to telomere being IL1A-IL1B-IL1F7-IL1F9-IL1F6-IL1F8-IL1F5-IL1F10-IL1RN, and that key features of exon boundaries are conserved across family members.\",\n      \"method\": \"Genomic sequencing, physical mapping, SNP and microsatellite marker mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — comprehensive sequence-based mapping, single consortium effort with multiple methods\",\n      \"pmids\": [\"11991722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL36RN (IL-1F5) antagonist activity requires N-terminal processing: removal of the N-terminal methionine to yield Val-2 as the start residue is required for full antagonist activity. Val-2-initiated IL-36Ra fully inhibits IL-36α, IL-36β, and IL-36γ. The mechanism of IL-36Ra antagonism is analogous to IL-1Ra: IL-36Ra binds to IL-1Rrp2 (IL-36R) and prevents IL-1RAcP recruitment, thereby blocking formation of a functional signaling complex.\",\n      \"method\": \"In vitro antagonist activity assays with N-terminally truncated recombinant proteins, chimeric receptor experiments, co-immunoprecipitation, cell-based signaling assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with mutagenesis, co-IP, chimeric receptor epistasis; multiple orthogonal methods in single study\",\n      \"pmids\": [\"21965679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL36RN (IL-1F5/IL-36Ra) expression is increased 2–3 orders of magnitude in psoriasis plaque skin versus uninvolved skin. IL-36Ra (IL-1F5) is induced in normal keratinocytes by IL-1α and TNF-α, and its expression decreases with etanercept treatment concomitant with clinical improvement, placing it as part of the IL-1F5/F6/F8/F9 signaling system active in inflammatory skin disease.\",\n      \"method\": \"Quantitative RT-PCR, immunohistochemistry, mouse models of psoriasis, microarray analysis of reconstituted human epidermis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — multiple expression methods plus functional microarray in tissue model, single lab\",\n      \"pmids\": [\"21242515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss-of-function mutations in IL36RN (p.Ser113Leu and p.Arg48Trp, altering evolutionarily conserved residues) cause generalized pustular psoriasis (GPP). Homozygosity for the p.Ser113Leu variant is associated with an elevated proinflammatory cytokine response following ex vivo stimulation with IL-36α, demonstrating that IL36RN loss of function leads to unopposed IL-36 signaling and systemic inflammation.\",\n      \"method\": \"Exome sequencing, Sanger validation, population genetics, ex vivo cytokine stimulation assay\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — exome sequencing combined with functional ex vivo assay demonstrating elevated proinflammatory response upon IL36RN loss, replicated across multiple subsequent studies\",\n      \"pmids\": [\"21839423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IL-36Ra (IL36RN protein) binds specifically to the IL-36 receptor (IL-1Rrp2) as demonstrated by screening immobilized extracellular domains of all IL-1 receptor family members, and has biological effects on immune cells (inhibiting IL-22 and IL-17 production from T lymphocytes and IL-8 from monocytes stimulated with IL-36γ) similar to those of IL-38 acting via the same receptor.\",\n      \"method\": \"Receptor-binding screen with immobilized extracellular domains of IL-1 receptor family members, PBMC cytokine production assays, dendritic cell activation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — direct receptor-binding screen across all IL-1R family members plus multiple functional assays in primary human cells\",\n      \"pmids\": [\"22315422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Homozygous or compound heterozygous IL36RN mutations account for the majority (9 of 11 cases) of GPP without psoriasis vulgaris in a Japanese cohort, establishing that GPP-alone is a distinct disease subtype caused by deficiency of IL-36 receptor antagonist, while GPP with psoriasis vulgaris has a different genetic etiology.\",\n      \"method\": \"IL36RN mutation screening by sequencing, genotype-phenotype correlation analysis\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic screening study with strong genotype-phenotype correlation but no direct functional assay of mutant proteins\",\n      \"pmids\": [\"23698098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes beyond GPP, including palmoplantar pustulosis and acrodermatitis continua of Hallopeau, extending the loss-of-function disease spectrum of IL36RN.\",\n      \"method\": \"Candidate gene sequencing, genotype-phenotype correlation\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic variant identification with phenotypic correlation, no in vitro functional assay of mutants\",\n      \"pmids\": [\"23303454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rare variations in IL36RN are found in patients with acute generalized exanthematous pustulosis (AGEP), a severe adverse drug reaction, suggesting that reduced IL-36 receptor antagonist function is a predisposing factor for this drug-induced pustular phenotype.\",\n      \"method\": \"Candidate gene sequencing in AGEP cases versus controls\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — genetic association with no functional validation of variants in pustular drug reaction context\",\n      \"pmids\": [\"23358093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-36Ra (IL36RN protein), produced by keratinocytes, acts to limit IL-36-driven skin inflammation: in the absence of adequate IL-36Ra, IL-36 cytokines drive expression of chemokines (CXCL1, CXCL8, CCL3, CCL5, CCL20) in keratinocytes and activate myeloid dendritic cells and monocytes via IL-36R, promoting myeloid cell infiltration and acanthosis.\",\n      \"method\": \"Human keratinocyte cytokine treatment, intradermal injection of IL-36α in mice, flow cytometry, ELISA, allogeneic T cell proliferation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo methods demonstrating IL-36Ra-opposed pathway, single lab\",\n      \"pmids\": [\"24829417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL36RN mutations (including p.Ser113Leu) define a severe autoinflammatory phenotype of GPP with systemic features, and some patients with IL36RN deficiency respond poorly to conventional psoriasis treatments but may benefit from IL-1 pathway blockade, further validating IL36RN loss-of-function as mechanistically driving IL-36 pathway overactivation.\",\n      \"method\": \"IL36RN sequencing, clinical phenotyping, treatment response analysis\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — clinical genotype-phenotype study, limited direct mechanistic experimentation\",\n      \"pmids\": [\"25458002\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL36RN encodes IL-36Ra, a secreted IL-1 family receptor antagonist that, following N-terminal processing (removal of the initiator methionine to expose Val-2), binds specifically to the IL-36 receptor (IL-1Rrp2/IL-1RL2) and blocks recruitment of the co-receptor IL-1RAcP, thereby preventing assembly of a functional signaling complex and opposing the pro-inflammatory activities of IL-36α, IL-36β, and IL-36γ; loss-of-function mutations in IL36RN result in unopposed IL-36 signaling in keratinocytes and myeloid cells, manifesting clinically as generalized pustular psoriasis and related pustular inflammatory diseases.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL36RN encodes a member of the IL-1 cytokine family with 52% amino acid identity to IL-1 receptor antagonist (IL-1Ra), mapped to the IL-1 gene cluster on chromosome 2q, with a conserved four-exon gene structure and alternatively spliced 5' UTR exons indicating origin by duplication of a primordial IL-1Ra gene [PMID:10512743, PMID:10866108]. Expression is predominantly restricted to epithelial cells, particularly skin, and is inducible in monocytic cells by PMA and LPS, consistent with a role in epithelial inflammatory responses [PMID:10512743, PMID:10860666]. Like intracellular IL-1Ra, IL36RN lacks a classical hydrophobic signal sequence [PMID:10866108].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of IL36RN as a new IL-1 family member established that a second IL-1Ra-like gene exists with predominant skin expression and inflammatory inducibility, raising the question of whether it functions as a receptor antagonist in epithelial contexts.\",\n      \"evidence\": \"EST database searching, cDNA cloning, chromosomal mapping, Northern blot, and PMA/LPS induction assay in THP-1 cells\",\n      \"pmids\": [\"10512743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional demonstration of receptor antagonist activity\",\n        \"Mechanism of secretion without a classical signal peptide is unknown\",\n        \"Cognate receptor not identified\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Determination of gene structure and tissue expression showed that IL36RN arose by duplication of the IL-1Ra gene and is restricted to epithelial populations, linking its biology specifically to barrier tissues rather than systemic immunity.\",\n      \"evidence\": \"Genomic sequencing (~7,600 nt), exon-intron boundary mapping, comparative gene structure analysis, and multi-tissue expression profiling by two independent groups\",\n      \"pmids\": [\"10866108\", \"10860666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct demonstration of antagonist activity on any IL-36 receptor\",\n        \"Protein-level expression and processing not characterized\",\n        \"Functional redundancy or distinction from IL-1Ra in skin not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether IL36RN directly antagonizes IL-36 receptor signaling, its mechanism of non-classical secretion, its protein-level regulation, and its role in skin inflammatory diseases remain to be mechanistically defined in the primary literature captured here.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No receptor binding or signaling inhibition data\",\n        \"No loss-of-function or gain-of-function studies\",\n        \"No structural or biophysical characterization of the protein\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0098772\",\n        \"supporting_discovery_ids\": [0, 1]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005829\",\n        \"supporting_discovery_ids\": [1]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-168256\",\n        \"supporting_discovery_ids\": [0, 2]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"IL36RN encodes interleukin-36 receptor antagonist (IL-36Ra), a secreted IL-1 family member that functions as a specific antagonist of the IL-36 signaling axis by binding the IL-36 receptor (IL-1Rrp2/IL-1RL2) and preventing recruitment of the co-receptor IL-1RAcP, thereby blocking NF-κB activation driven by IL-36α, IL-36β, and IL-36γ [PMID:11466363, PMID:21965679, PMID:22315422]. Full antagonist activity requires N-terminal processing—removal of the initiator methionine to expose Val-2—and the mature protein adopts an IL-1Ra-like β-trefoil fold, consistent with its origin by duplication of a primordial IL-1 receptor antagonist gene [PMID:21965679, PMID:10744718, PMID:10866108]. IL-36Ra is predominantly expressed in keratinocytes and squamous epithelia, is induced by pro-inflammatory stimuli (IL-1α, TNF-α, IFN-γ), and limits IL-36-driven chemokine production and myeloid cell recruitment in the skin [PMID:10744718, PMID:21242515, PMID:24829417]. Loss-of-function mutations in IL36RN cause deficiency of IL-36 receptor antagonist (DITRA), manifesting as generalized pustular psoriasis and related pustular inflammatory phenotypes due to unopposed IL-36 signaling [PMID:21839423, PMID:23698098].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of IL36RN as a novel IL-1 receptor antagonist family member established that a second receptor antagonist gene existed within the IL-1 locus, raising the question of which receptor system it controlled.\",\n      \"evidence\": \"cDNA cloning, chromosomal mapping, Northern blot in skin and THP-1 cells\",\n      \"pmids\": [\"10512743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Target receptor unknown\",\n        \"No demonstration of antagonist activity\",\n        \"Processing and activation requirements uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Concurrent genomic, structural, and expression studies from multiple groups confirmed IL36RN as a bona fide IL-1 family member with an IL-1Ra-like fold, conserved exon-intron structure indicating gene duplication origin, and highly restricted epithelial expression, resolving its evolutionary relationship but not its function.\",\n      \"evidence\": \"Genomic sequencing, circular dichroism spectroscopy, protein structure modeling, expression profiling across tissues\",\n      \"pmids\": [\"10860666\", \"10866108\", \"10625660\", \"10744718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional antagonism not yet demonstrated in any assay\",\n        \"Cognate receptor and agonists not identified\",\n        \"Biological role in skin immunity not established\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Reporter assays demonstrated that IL-36Ra specifically antagonizes IL-36γ-mediated NF-κB activation through IL-1Rrp2, establishing IL-36Ra/IL-36γ/IL-1Rrp2 as an independent IL-1 family signaling axis analogous to IL-1Ra/IL-1/IL-1R1.\",\n      \"evidence\": \"NF-κB-luciferase reporter assay with receptor specificity panels, quantitative RT-PCR\",\n      \"pmids\": [\"11466363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of antagonism (co-receptor blockade vs. competitive displacement) not resolved\",\n        \"N-terminal processing requirements unknown\",\n        \"Antagonism of IL-36α and IL-36β not tested\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Biochemical reconstitution showed that IL-36Ra requires N-terminal methionine removal to achieve full antagonist potency and that it blocks signaling by preventing IL-1RAcP recruitment to the IL-36R, resolving the molecular mechanism of antagonism and extending it to all three IL-36 agonists.\",\n      \"evidence\": \"Truncation mutagenesis of recombinant proteins, chimeric receptor experiments, co-immunoprecipitation, cell-based signaling assays\",\n      \"pmids\": [\"21965679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Protease responsible for N-terminal processing in vivo not identified\",\n        \"Structural basis of receptor binding at atomic resolution not determined\",\n        \"Stoichiometry and kinetics of receptor complex blockade not measured\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Two discoveries converged to establish IL36RN in human disease: expression profiling showed massive IL-36Ra upregulation in psoriatic skin, while exome sequencing identified homozygous loss-of-function mutations (p.Ser113Leu, p.Arg48Trp) as the cause of generalized pustular psoriasis, with ex vivo demonstration of unopposed IL-36 signaling in mutation carriers.\",\n      \"evidence\": \"qRT-PCR and immunohistochemistry in psoriatic lesions; exome sequencing with Sanger validation and ex vivo cytokine stimulation assay in patient PBMCs\",\n      \"pmids\": [\"21242515\", \"21839423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural impact of individual missense mutations not resolved\",\n        \"Whether partial loss-of-function alleles contribute to common psoriasis unknown\",\n        \"Cell-type-specific contribution (keratinocyte vs. myeloid) to disease pathogenesis not delineated\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"A systematic receptor-binding screen across all IL-1 receptor family members confirmed exclusive IL-36Ra binding to IL-1Rrp2 and demonstrated functional suppression of IL-22, IL-17, and IL-8 production from primary human immune cells, establishing physiological anti-inflammatory effects beyond keratinocytes.\",\n      \"evidence\": \"Immobilized extracellular domain binding screen, PBMC and dendritic cell cytokine assays\",\n      \"pmids\": [\"22315422\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative contribution of IL-36Ra vs. IL-38 at the same receptor not resolved\",\n        \"In vivo immune cell targets in human tissue not mapped\",\n        \"Binding affinity and receptor occupancy not quantified\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Expanded genetic studies established that IL36RN mutations account for the majority of GPP-without-psoriasis-vulgaris cases and that the disease spectrum extends to palmoplantar pustulosis and acrodermatitis continua of Hallopeau, defining DITRA as a distinct autoinflammatory entity.\",\n      \"evidence\": \"IL36RN mutation screening by sequencing in Japanese and European cohorts, genotype-phenotype correlation\",\n      \"pmids\": [\"23698098\", \"23303454\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro functional assessment of most identified mutant proteins\",\n        \"Genetic modifiers and incomplete penetrance factors uncharacterized\",\n        \"Whether heterozygous carriers have subclinical phenotype not established\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Functional studies in keratinocytes and mouse models defined the downstream effector pathway: in the absence of IL-36Ra, IL-36 agonists drive expression of neutrophil-attracting chemokines (CXCL1, CXCL8, CCL20) and activate myeloid dendritic cells, explaining the neutrophilic pustular pathology of DITRA.\",\n      \"evidence\": \"Keratinocyte cytokine treatment, intradermal IL-36α injection in mice, flow cytometry, ELISA\",\n      \"pmids\": [\"24829417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Contribution of adaptive immunity and specific T cell subsets downstream of IL-36 not defined\",\n        \"Whether IL-36Ra directly modulates neutrophil function unknown\",\n        \"Tissue-specific regulatory mechanisms controlling IL-36Ra expression not identified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the protease(s) that process IL-36Ra N-terminally in vivo, the atomic-resolution structure of the IL-36Ra–IL-36R complex, and the mechanistic basis by which specific IL36RN missense mutations differentially affect protein stability versus receptor binding.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo processing protease not identified\",\n        \"No crystal or cryo-EM structure of IL-36Ra bound to IL-36R\",\n        \"Structure-function relationship of disease-causing missense mutations not systematically characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 7, 10]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [5, 7, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 4, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 7, 10, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 11, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IL1RL2\",\n      \"IL1RAP\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}