{"gene":"IL36B","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2000,"finding":"IL36B (then named FIL1eta/IL-1F8) was identified as a novel IL-1 family member through sequence similarity searches. It shares significant amino acid similarity with IL-1α, IL-1β, IL-1Ra, and IL-18, maintains the conserved exon-intron arrangement of the IL-1 family, and protein structure modeling indicates structural relatedness to IL-1β and IL-1Ra. The gene clusters with other IL-1 family members on human chromosome 2q.","method":"cDNA cloning, sequence homology analysis, protein structure modeling, chromosomal mapping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — original cloning and structural prediction, single study","pmids":["10625660"],"is_preprint":false},{"year":2001,"finding":"IL36B (then named IL-1epsilon) activates NF-κB through the orphan receptor IL-1 receptor-related protein 2 (IL-1Rrp2), but not through classical IL-1R pairs. This signaling was demonstrated in NF-κB-luciferase reporter assays and shown to be specific, as IL-1delta (IL-36Ra) antagonizes this response. Expression is restricted to keratinocytes among skin-derived cells.","method":"NF-κB-luciferase reporter assay, cell transfection, quantitative RT-PCR","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — functional reporter assay with receptor specificity demonstrated, single lab","pmids":["11466363"],"is_preprint":false},{"year":2004,"finding":"IL36B (IL-1F8) signals through both IL-1Rrp2 and IL-1RAcP to activate the NF-κB and MAPK (JNK, ERK1/2) pathways. Antibodies against IL-1RAcP and transfection of cytoplasmically deleted IL-1RAcP both blocked NF-κB activation by IL-1F8, demonstrating that IL-1RAcP is required as a co-receptor. Downstream, IL-1F8 activated an IL-8 promoter reporter and induced IL-6 secretion in NCI/ADR-RES cells.","method":"NF-κB reporter assay, receptor-blocking antibodies, dominant-negative IL-1RAcP transfection, ELISA","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (antibody blockade, dominant-negative, reporter assay) in multiple cell lines","pmids":["14734551"],"is_preprint":false},{"year":2006,"finding":"IL36B (IL-1F8) stimulates production of pro-inflammatory mediators (including IL-6 and matrix metalloproteinases) in primary human synovial fibroblasts and articular chondrocytes, which naturally express its receptor IL-1Rrp2. This establishes IL36B as functionally active in joint cells.","method":"Primary cell culture, cytokine measurement (ELISA), mRNA expression analysis, receptor expression profiling","journal":"Arthritis research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 — functional response in primary human cells with receptor expression confirmed, single lab","pmids":["16646978"],"is_preprint":false},{"year":2011,"finding":"N-terminal truncation of IL36B (IL-36β) to the conserved A-X-Asp motif dramatically increases its specific activity by ~10³–10⁴-fold (EC₅₀ shifting from ~1 μg/ml to ~1 ng/ml), demonstrating that proteolytic processing of the N-terminus is required for full agonist activity. IL-36Ra antagonizes processed IL-36β by binding IL-1Rrp2 and preventing co-immunoprecipitation of IL-1RAcP with IL-1Rrp2, blocking formation of the functional signaling complex — analogous to IL-1Ra inhibition of IL-1β.","method":"N-terminal truncation mutagenesis, NF-κB reporter assay, co-immunoprecipitation, chimeric receptor experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — reconstitution with truncation mutagenesis, co-IP mechanistic validation, multiple orthogonal approaches in single rigorous study","pmids":["21965679"],"is_preprint":false},{"year":2011,"finding":"IL36B (IL-1F8) induces expression and secretion of antimicrobial peptides (human β-defensin-2, HBD-3) and matrix metalloproteinases in reconstituted human epidermis. IL-1α and TNF-α induce IL-1F8 transcript expression in normal human keratinocytes, placing IL36B downstream of classical pro-inflammatory cytokine signaling in the skin.","method":"Quantitative RT-PCR, immunohistochemistry, microarray analysis, reconstituted human epidermis model, protein secretion assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — functional induction of antimicrobial peptides demonstrated in 3D epidermal model, single lab","pmids":["21242515"],"is_preprint":false},{"year":2014,"finding":"IL36B (IL-36β), along with other IL-36 cytokines, induces expression of chemokines CXCL1, CXCL8, CCL3, CCL5, and CCL20 in human keratinocytes, and blood monocytes and myeloid dendritic cells (mDC) express the IL-36 receptor and respond functionally to IL-36, upregulating CD83, CD86, HLA-DR and secreting IL-1β and IL-6. IL-36-treated monocyte-derived DCs enhanced allogeneic CD4+ T cell proliferation, demonstrating IL-36's role in bridging innate and adaptive immunity in skin.","method":"Primary cell culture, flow cytometry, ELISA, intradermal injection mouse model, T cell proliferation assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple cell types and in vivo validation, but IL-36 cytokines used together without exclusive IL36B-specific readout in all experiments","pmids":["24829417"],"is_preprint":false},{"year":2017,"finding":"IL36B (IL-36β), along with IL-36α and IL-36γ, directly acts on human lung fibroblasts and bronchial epithelial cells (which express IL-36R) to upregulate IL-6 and CXCL8 gene expression and protein secretion. This induction is mediated through p38MAPK, ERK, and Akt signaling pathways.","method":"Cell culture, qRT-PCR, ELISA, pharmacological signaling pathway inhibitors (p38MAPK, ERK, Akt inhibitors)","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 — pathway inhibitor experiments identify downstream signaling, but IL-36 isoforms not always distinguished individually","pmids":["28869889"],"is_preprint":false}],"current_model":"IL36B (IL-36β) is a pro-inflammatory IL-1 family cytokine that requires N-terminal proteolytic processing for full activity; the processed form signals through a heterodimeric receptor complex of IL-1Rrp2 (IL-1RL2) and IL-1RAcP to activate NF-κB and MAPK (JNK, ERK1/2) pathways, inducing downstream chemokines, antimicrobial peptides, and pro-inflammatory cytokines in keratinocytes, synovial fibroblasts, chondrocytes, and lung epithelial cells; IL-36Ra antagonizes this signaling by binding IL-1Rrp2 and preventing IL-1RAcP recruitment."},"narrative":{"teleology":[{"year":2000,"claim":"Identification of IL36B as a novel IL-1 family member resolved whether additional cytokines with IL-1-like fold existed in the chromosome 2q cluster.","evidence":"cDNA cloning, sequence homology analysis, and protein structure modeling showing structural relatedness to IL-1β/IL-1Ra","pmids":["10625660"],"confidence":"Medium","gaps":["No functional activity or receptor identified at this stage","Expression pattern beyond transcript detection unknown"]},{"year":2001,"claim":"Demonstration that IL36B activates NF-κB specifically through the orphan receptor IL-1Rrp2 established its cognate receptor and distinguished it from classical IL-1 signaling.","evidence":"NF-κB-luciferase reporter assay with receptor panel screening in transfected cells","pmids":["11466363"],"confidence":"Medium","gaps":["Whether a co-receptor is needed was not addressed","Signaling pathways beyond NF-κB not yet mapped"]},{"year":2004,"claim":"Identification of IL-1RAcP as an essential co-receptor for IL-36β signaling completed the receptor complex architecture and revealed activation of both NF-κB and MAPK (JNK, ERK1/2) cascades.","evidence":"Anti-IL-1RAcP blocking antibodies, dominant-negative IL-1RAcP transfection, and NF-κB/IL-8 reporter assays in NCI/ADR-RES cells","pmids":["14734551"],"confidence":"High","gaps":["Identity of the protease(s) activating the full-length precursor unknown","Structural basis for IL-1Rrp2/IL-1RAcP heterodimerization not resolved"]},{"year":2006,"claim":"Demonstration that primary synovial fibroblasts and chondrocytes respond to IL-36β extended its functional relevance beyond skin to joint inflammation.","evidence":"Cytokine (IL-6, MMP) measurement by ELISA and receptor expression profiling in primary human joint cells","pmids":["16646978"],"confidence":"Medium","gaps":["In vivo relevance in joint disease models not tested","Relative contribution of IL-36β versus other IL-36 family members in joints unclear"]},{"year":2011,"claim":"Defining the N-terminal A-X-Asp processing requirement resolved a long-standing question about why recombinant full-length IL-36β showed weak activity, and co-IP experiments showed IL-36Ra antagonizes signaling by blocking IL-1RAcP recruitment to IL-1Rrp2.","evidence":"Systematic N-terminal truncation mutagenesis with NF-κB reporter dose-response and co-immunoprecipitation of receptor subunits","pmids":["21965679"],"confidence":"High","gaps":["The endogenous protease(s) responsible for N-terminal cleavage in vivo remain unidentified","Whether processing occurs intracellularly or extracellularly is unknown"]},{"year":2011,"claim":"Showing that IL-36β induces antimicrobial peptides (β-defensin-2, HBD-3) in reconstituted human epidermis established its role in cutaneous antimicrobial defense and placed it downstream of IL-1α/TNF-α signaling.","evidence":"qRT-PCR, immunohistochemistry, and secretion assays in 3D reconstituted human epidermis model","pmids":["21242515"],"confidence":"Medium","gaps":["In vivo antimicrobial efficacy not demonstrated","Whether IL-36β acts on immune cells in skin besides keratinocytes not addressed"]},{"year":2014,"claim":"Demonstrating that IL-36 cytokines activate monocytes and myeloid dendritic cells to promote T cell proliferation established IL-36β as a bridge between innate and adaptive immunity.","evidence":"Flow cytometry for surface markers, ELISA for cytokines, allogeneic CD4+ T cell proliferation assay, and intradermal injection mouse model","pmids":["24829417"],"confidence":"Medium","gaps":["IL-36β-specific contributions were not always distinguished from other IL-36 isoforms","Whether dendritic cell activation requires processed IL-36β specifically was not tested"]},{"year":2017,"claim":"Identification of p38 MAPK, ERK, and Akt as signaling mediators in lung fibroblasts and bronchial epithelial cells extended IL-36β activity to pulmonary tissue and broadened the known downstream signaling repertoire.","evidence":"Pharmacological inhibitors of p38MAPK, ERK, and Akt combined with qRT-PCR and ELISA in primary lung cells","pmids":["28869889"],"confidence":"Medium","gaps":["IL-36 isoform-specific effects in lung were not fully resolved","In vivo pulmonary disease relevance not demonstrated"]},{"year":null,"claim":"The identity of the endogenous protease(s) that cleave IL-36β to its active form in vivo, the structural basis for the IL-36β/IL-1Rrp2/IL-1RAcP ternary complex, and IL-36β-specific (versus pan-IL-36) contributions in disease remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Endogenous activating protease(s) not identified","No crystal structure of IL-36β bound to its receptor complex","IL-36β-specific versus redundant functions with IL-36α/γ not delineated in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,2,4]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,5,6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,4,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,7]}],"complexes":[],"partners":["IL1RL2","IL1RAP"],"other_free_text":[]},"mechanistic_narrative":"IL-36β (IL36B) is a pro-inflammatory cytokine of the IL-1 family that requires N-terminal proteolytic processing at a conserved A-X-Asp motif to attain full agonist activity, increasing potency by approximately 1,000–10,000-fold [PMID:21965679]. The processed cytokine signals through a heterodimeric receptor comprising IL-1Rrp2 (IL-1RL2) and the co-receptor IL-1RAcP, activating NF-κB, JNK, ERK1/2, p38 MAPK, and Akt pathways to induce downstream mediators including IL-6, IL-8/CXCL8, antimicrobial peptides (β-defensins), matrix metalloproteinases, and multiple chemokines in keratinocytes, synovial fibroblasts, chondrocytes, and lung epithelial cells [PMID:14734551, PMID:21242515, PMID:28869889]. IL-36Ra antagonizes IL-36β signaling by binding IL-1Rrp2 and preventing recruitment of IL-1RAcP, thereby blocking formation of the functional signaling complex [PMID:21965679]. IL-36β also acts on monocytes and myeloid dendritic cells to promote their maturation and cytokine secretion, bridging innate and adaptive immune responses [PMID:24829417]."},"prefetch_data":{"uniprot":{"accession":"Q9NZH7","full_name":"Interleukin-36 beta","aliases":["FIL1 eta","Interleukin-1 eta","IL-1 eta","Interleukin-1 family member 8","IL-1F8","Interleukin-1 homolog 2","IL-1H2"],"length_aa":164,"mass_kda":18.5,"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. Stimulates production of interleukin-6 and interleukin-8 in synovial fibrobasts, articular chondrocytes and mature adipocytes. Induces expression of a number of antimicrobial peptides including beta-defensins 4 and 103 as well as a number of matrix metalloproteases. 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","subcellular_location":"Cytoplasm; Secreted","url":"https://www.uniprot.org/uniprotkb/Q9NZH7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL36B","classification":"Not Classified","n_dependent_lines":17,"n_total_lines":1208,"dependency_fraction":0.014072847682119206},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL36B","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":"605508","title":"INTERLEUKIN 36, BETA; IL36B","url":"https://www.omim.org/entry/605508"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"esophagus","ntpm":2.1},{"tissue":"lymphoid tissue","ntpm":3.5},{"tissue":"skin 1","ntpm":8.0}],"url":"https://www.proteinatlas.org/search/IL36B"},"hgnc":{"alias_symbol":["FIL1","IL-1H2","IL-1F8","FILI-(ETA)","IL1-ETA","IL1H2","MGC126880","MGC126882"],"prev_symbol":["IL1F8"]},"alphafold":{"accession":"Q9NZH7","domains":[{"cath_id":"2.80.10.50","chopping":"11-127","consensus_level":"medium","plddt":62.5806,"start":11,"end":127}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZH7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZH7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZH7-F1-predicted_aligned_error_v6.png","plddt_mean":55.28},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL36B","jax_strain_url":"https://www.jax.org/strain/search?query=IL36B"},"sequence":{"accession":"Q9NZH7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NZH7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NZH7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZH7"}},"corpus_meta":[{"pmid":"32413576","id":"PMC_32413576","title":"Chip-based 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cancer?","date":"2020","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32013927","citation_count":30,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28811383","id":"PMC_28811383","title":"Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling.","date":"2017","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/28811383","citation_count":30,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":2441,"output_tokens":34,"usd":0.003916},"stage2":{"model":"","input_tokens":0,"output_tokens":0,"usd":0.0},"total_usd":0.181964,"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":16584,"output_tokens":3587,"usd":0.051778},"round2_rules_fired":"R1","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5841,"output_tokens":2199,"usd":0.12627}},"stage1_raw":"```json\n{\n  \"discoveries\": [],\n  \"current_model\": \"No mechanistic findings in the available literature.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEPT papers.\n\n**Classification:**\n\n- [1] (PMID:32413576) — Proteomics/stroke study; mentions \"IL-1F8/FIL1 eta\" as a downregulated protein in stroke serum. This is an expression/biomarker study with no mechanistic findings about IL36B. EXCLUDE (no mechanism).\n- gene2pubmed [1] PMID:12477932 — MGC cDNA sequencing. No mechanism. EXCLUDE.\n- gene2pubmed [2] PMID:33961781 — BioPlex interactome. Potential IL36B interactions detected by AP-MS. KEEP (interactome data).\n- gene2pubmed [3] PMID:21873635 — GO annotation. EXCLUDE.\n- gene2pubmed [4] PMID:14734551 — IL-1F6, IL-1F8 (=IL36B), IL-1F9 signal through IL-1Rrp2 and IL-1RAcP → NF-κB/MAPKs. KEEP.\n- gene2pubmed [5] PMID:21965679 — N-terminal processing required for full IL-36β activity; IL-36Ra antagonism mechanism. KEEP.\n- gene2pubmed [6] PMID:8188271 — Physical map of IL-1 cluster. Genomics/mapping only. EXCLUDE.\n- gene2pubmed [7] PMID:10625660 — Cloning of FIL1eta (=IL36B). Initial characterization. KEEP.\n- gene2pubmed [8] PMID:10744718 — Cloning IL-1H1/H2/H3/H4. IL-1H1 may be IL36A or related. No specific IL36B mechanism. EXCLUDE (focuses on different members).\n- gene2pubmed [9] PMID:21242515 — IL-1F8 (IL36B) induces antimicrobial peptides in keratinocytes; psoriasis context. KEEP.\n- gene2pubmed [10] PMID:24829417 — IL-36 cytokines (including IL-36β) promote myeloid cell infiltration; keratinocyte chemokine induction. KEEP.\n- gene2pubmed [11] PMID:11466363 — IL-1epsilon (=IL36B) activates NF-κB through IL-1Rrp2. KEEP.\n- gene2pubmed [12] PMID:11145836 — IL-1H binds IL-18 receptor. This appears to be IL-1F7/IL-37, not IL36B. EXCLUDE.\n- gene2pubmed [13] PMID:11278614 — IL-1HY2 binds IL-1RI. Different family member. EXCLUDE.\n- gene2pubmed [14] PMID:11991722 — Sequence map of IL-1 cluster; gene order includes IL1F8. Genomics only. EXCLUDE.\n- gene2pubmed [15] PMID:10860666 — IL-1RP cloning; expression restricted to epithelia. IL-1RP2 = IL36B? Limited mechanism. KEEP (initial characterization).\n- gene2pubmed [16] PMID:11574262 — Nomenclature paper. EXCLUDE.\n- gene2pubmed [17] PMID:31736959 — Review of IL-36 signaling. KEEP for mechanistic summary grounded in cited literature.\n- gene2pubmed [18] PMID:16646978 — IL-1F8 (IL36B) stimulates pro-inflammatory mediators in synovial fibroblasts and chondrocytes via IL-1Rrp2. KEEP.\n- gene2pubmed [19] PMID:22318382 — IL-36γ (not IL36B). Focuses on IL-36γ release mechanism. EXCLUDE (IL36G, not IL36B).\n- gene2pubmed [20] PMID:10512743 — IL1HY1 = IL-1Ra homolog. Not IL36B. EXCLUDE.\n- gene2pubmed [21] PMID:20237496 — GWAS/vaccine response. EXCLUDE.\n- gene2pubmed [22] PMID:15815621 — Chromosome 2 sequencing. EXCLUDE.\n- gene2pubmed [23] PMID:23824909 — BAG3 interactome. Not IL36B. EXCLUDE.\n- gene2pubmed [24] PMID:38189700 — Review IL-36 in skin diseases; includes IL36B mechanistic context. KEEP.\n- gene2pubmed [25] PMID:28869889 — IL-36β induces IL-6/CXCL8 in lung cells via p38MAPK/ERK/Akt. KEEP.\n- gene2pubmed [26] PMID:9169134 — Physical map of IL-1 cluster. EXCLUDE.\n- gene2pubmed [27] PMID:11093146 — IL-1L1 lacks IL-1/IL-18 activities. Different member. EXCLUDE.\n- gene2pubmed [28] PMID:20141484 — SNP association study. EXCLUDE.\n- gene2pubmed [29] PMID:32013927 — IHC/survival analysis. EXCLUDE.\n- gene2pubmed [30] PMID:28811383 — IL-36 immune evasion hypothesis review. KEEP for mechanistic context.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"IL36B (then named FIL1eta/IL-1F8) was identified as a novel IL-1 family member through sequence similarity searches. It shares significant amino acid similarity with IL-1α, IL-1β, IL-1Ra, and IL-18, maintains the conserved exon-intron arrangement of the IL-1 family, and protein structure modeling indicates structural relatedness to IL-1β and IL-1Ra. The gene clusters with other IL-1 family members on human chromosome 2q.\",\n      \"method\": \"cDNA cloning, sequence homology analysis, protein structure modeling, chromosomal mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — original cloning and structural prediction, single study\",\n      \"pmids\": [\"10625660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IL36B (then named IL-1epsilon) activates NF-κB through the orphan receptor IL-1 receptor-related protein 2 (IL-1Rrp2), but not through classical IL-1R pairs. This signaling was demonstrated in NF-κB-luciferase reporter assays and shown to be specific, as IL-1delta (IL-36Ra) antagonizes this response. Expression is restricted to keratinocytes among skin-derived cells.\",\n      \"method\": \"NF-κB-luciferase reporter assay, cell transfection, quantitative RT-PCR\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reporter assay with receptor specificity demonstrated, single lab\",\n      \"pmids\": [\"11466363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL36B (IL-1F8) signals through both IL-1Rrp2 and IL-1RAcP to activate the NF-κB and MAPK (JNK, ERK1/2) pathways. Antibodies against IL-1RAcP and transfection of cytoplasmically deleted IL-1RAcP both blocked NF-κB activation by IL-1F8, demonstrating that IL-1RAcP is required as a co-receptor. Downstream, IL-1F8 activated an IL-8 promoter reporter and induced IL-6 secretion in NCI/ADR-RES cells.\",\n      \"method\": \"NF-κB reporter assay, receptor-blocking antibodies, dominant-negative IL-1RAcP transfection, ELISA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (antibody blockade, dominant-negative, reporter assay) in multiple cell lines\",\n      \"pmids\": [\"14734551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL36B (IL-1F8) stimulates production of pro-inflammatory mediators (including IL-6 and matrix metalloproteinases) in primary human synovial fibroblasts and articular chondrocytes, which naturally express its receptor IL-1Rrp2. This establishes IL36B as functionally active in joint cells.\",\n      \"method\": \"Primary cell culture, cytokine measurement (ELISA), mRNA expression analysis, receptor expression profiling\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional response in primary human cells with receptor expression confirmed, single lab\",\n      \"pmids\": [\"16646978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"N-terminal truncation of IL36B (IL-36β) to the conserved A-X-Asp motif dramatically increases its specific activity by ~10³–10⁴-fold (EC₅₀ shifting from ~1 μg/ml to ~1 ng/ml), demonstrating that proteolytic processing of the N-terminus is required for full agonist activity. IL-36Ra antagonizes processed IL-36β by binding IL-1Rrp2 and preventing co-immunoprecipitation of IL-1RAcP with IL-1Rrp2, blocking formation of the functional signaling complex — analogous to IL-1Ra inhibition of IL-1β.\",\n      \"method\": \"N-terminal truncation mutagenesis, NF-κB reporter assay, co-immunoprecipitation, chimeric receptor experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution with truncation mutagenesis, co-IP mechanistic validation, multiple orthogonal approaches in single rigorous study\",\n      \"pmids\": [\"21965679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL36B (IL-1F8) induces expression and secretion of antimicrobial peptides (human β-defensin-2, HBD-3) and matrix metalloproteinases in reconstituted human epidermis. IL-1α and TNF-α induce IL-1F8 transcript expression in normal human keratinocytes, placing IL36B downstream of classical pro-inflammatory cytokine signaling in the skin.\",\n      \"method\": \"Quantitative RT-PCR, immunohistochemistry, microarray analysis, reconstituted human epidermis model, protein secretion assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional induction of antimicrobial peptides demonstrated in 3D epidermal model, single lab\",\n      \"pmids\": [\"21242515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL36B (IL-36β), along with other IL-36 cytokines, induces expression of chemokines CXCL1, CXCL8, CCL3, CCL5, and CCL20 in human keratinocytes, and blood monocytes and myeloid dendritic cells (mDC) express the IL-36 receptor and respond functionally to IL-36, upregulating CD83, CD86, HLA-DR and secreting IL-1β and IL-6. IL-36-treated monocyte-derived DCs enhanced allogeneic CD4+ T cell proliferation, demonstrating IL-36's role in bridging innate and adaptive immunity in skin.\",\n      \"method\": \"Primary cell culture, flow cytometry, ELISA, intradermal injection mouse model, T cell proliferation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell types and in vivo validation, but IL-36 cytokines used together without exclusive IL36B-specific readout in all experiments\",\n      \"pmids\": [\"24829417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL36B (IL-36β), along with IL-36α and IL-36γ, directly acts on human lung fibroblasts and bronchial epithelial cells (which express IL-36R) to upregulate IL-6 and CXCL8 gene expression and protein secretion. This induction is mediated through p38MAPK, ERK, and Akt signaling pathways.\",\n      \"method\": \"Cell culture, qRT-PCR, ELISA, pharmacological signaling pathway inhibitors (p38MAPK, ERK, Akt inhibitors)\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway inhibitor experiments identify downstream signaling, but IL-36 isoforms not always distinguished individually\",\n      \"pmids\": [\"28869889\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL36B (IL-36β) is a pro-inflammatory IL-1 family cytokine that requires N-terminal proteolytic processing for full activity; the processed form signals through a heterodimeric receptor complex of IL-1Rrp2 (IL-1RL2) and IL-1RAcP to activate NF-κB and MAPK (JNK, ERK1/2) pathways, inducing downstream chemokines, antimicrobial peptides, and pro-inflammatory cytokines in keratinocytes, synovial fibroblasts, chondrocytes, and lung epithelial cells; IL-36Ra antagonizes this signaling by binding IL-1Rrp2 and preventing IL-1RAcP recruitment.\"\n}\n```","stage2_raw":"\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"IL-36β (IL36B) is a pro-inflammatory cytokine of the IL-1 family that requires N-terminal proteolytic processing at a conserved A-X-Asp motif to attain full agonist activity, increasing potency by approximately 1,000–10,000-fold [PMID:21965679]. The processed cytokine signals through a heterodimeric receptor comprising IL-1Rrp2 (IL-1RL2) and the co-receptor IL-1RAcP, activating NF-κB, JNK, ERK1/2, p38 MAPK, and Akt pathways to induce downstream mediators including IL-6, IL-8/CXCL8, antimicrobial peptides (β-defensins), matrix metalloproteinases, and multiple chemokines in keratinocytes, synovial fibroblasts, chondrocytes, and lung epithelial cells [PMID:14734551, PMID:21242515, PMID:28869889]. IL-36Ra antagonizes IL-36β signaling by binding IL-1Rrp2 and preventing recruitment of IL-1RAcP, thereby blocking formation of the functional signaling complex [PMID:21965679]. IL-36β also acts on monocytes and myeloid dendritic cells to promote their maturation and cytokine secretion, bridging innate and adaptive immune responses [PMID:24829417].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of IL36B as a novel IL-1 family member resolved whether additional cytokines with IL-1-like fold existed in the chromosome 2q cluster.\",\n      \"evidence\": \"cDNA cloning, sequence homology analysis, and protein structure modeling showing structural relatedness to IL-1β/IL-1Ra\",\n      \"pmids\": [\"10625660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional activity or receptor identified at this stage\",\n        \"Expression pattern beyond transcript detection unknown\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstration that IL36B activates NF-κB specifically through the orphan receptor IL-1Rrp2 established its cognate receptor and distinguished it from classical IL-1 signaling.\",\n      \"evidence\": \"NF-κB-luciferase reporter assay with receptor panel screening in transfected cells\",\n      \"pmids\": [\"11466363\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether a co-receptor is needed was not addressed\",\n        \"Signaling pathways beyond NF-κB not yet mapped\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of IL-1RAcP as an essential co-receptor for IL-36β signaling completed the receptor complex architecture and revealed activation of both NF-κB and MAPK (JNK, ERK1/2) cascades.\",\n      \"evidence\": \"Anti-IL-1RAcP blocking antibodies, dominant-negative IL-1RAcP transfection, and NF-κB/IL-8 reporter assays in NCI/ADR-RES cells\",\n      \"pmids\": [\"14734551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the protease(s) activating the full-length precursor unknown\",\n        \"Structural basis for IL-1Rrp2/IL-1RAcP heterodimerization not resolved\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstration that primary synovial fibroblasts and chondrocytes respond to IL-36β extended its functional relevance beyond skin to joint inflammation.\",\n      \"evidence\": \"Cytokine (IL-6, MMP) measurement by ELISA and receptor expression profiling in primary human joint cells\",\n      \"pmids\": [\"16646978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo relevance in joint disease models not tested\",\n        \"Relative contribution of IL-36β versus other IL-36 family members in joints unclear\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defining the N-terminal A-X-Asp processing requirement resolved a long-standing question about why recombinant full-length IL-36β showed weak activity, and co-IP experiments showed IL-36Ra antagonizes signaling by blocking IL-1RAcP recruitment to IL-1Rrp2.\",\n      \"evidence\": \"Systematic N-terminal truncation mutagenesis with NF-κB reporter dose-response and co-immunoprecipitation of receptor subunits\",\n      \"pmids\": [\"21965679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The endogenous protease(s) responsible for N-terminal cleavage in vivo remain unidentified\",\n        \"Whether processing occurs intracellularly or extracellularly is unknown\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showing that IL-36β induces antimicrobial peptides (β-defensin-2, HBD-3) in reconstituted human epidermis established its role in cutaneous antimicrobial defense and placed it downstream of IL-1α/TNF-α signaling.\",\n      \"evidence\": \"qRT-PCR, immunohistochemistry, and secretion assays in 3D reconstituted human epidermis model\",\n      \"pmids\": [\"21242515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo antimicrobial efficacy not demonstrated\",\n        \"Whether IL-36β acts on immune cells in skin besides keratinocytes not addressed\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that IL-36 cytokines activate monocytes and myeloid dendritic cells to promote T cell proliferation established IL-36β as a bridge between innate and adaptive immunity.\",\n      \"evidence\": \"Flow cytometry for surface markers, ELISA for cytokines, allogeneic CD4+ T cell proliferation assay, and intradermal injection mouse model\",\n      \"pmids\": [\"24829417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"IL-36β-specific contributions were not always distinguished from other IL-36 isoforms\",\n        \"Whether dendritic cell activation requires processed IL-36β specifically was not tested\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of p38 MAPK, ERK, and Akt as signaling mediators in lung fibroblasts and bronchial epithelial cells extended IL-36β activity to pulmonary tissue and broadened the known downstream signaling repertoire.\",\n      \"evidence\": \"Pharmacological inhibitors of p38MAPK, ERK, and Akt combined with qRT-PCR and ELISA in primary lung cells\",\n      \"pmids\": [\"28869889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"IL-36 isoform-specific effects in lung were not fully resolved\",\n        \"In vivo pulmonary disease relevance not demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the endogenous protease(s) that cleave IL-36β to its active form in vivo, the structural basis for the IL-36β/IL-1Rrp2/IL-1RAcP ternary complex, and IL-36β-specific (versus pan-IL-36) contributions in disease remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Endogenous activating protease(s) not identified\",\n        \"No crystal structure of IL-36β bound to its receptor complex\",\n        \"IL-36β-specific versus redundant functions with IL-36α/γ not delineated in vivo\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 4, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IL1RL2\",\n      \"IL1RAP\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}