{"gene":"IL18RAP","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1998,"finding":"IL18RAP (AcPL) is a required co-receptor subunit for IL-18 signaling: both IL-1R-rp1 (IL-18R1) and AcPL must be co-expressed to induce NF-κB activity and activate JNK in response to IL-18. AcPL alone cannot bind IL-18 with appreciable affinity; a dominant-negative AcPL specifically inhibits IL-18 signaling, establishing its non-redundant role in signal transduction.","method":"Transient transfection assays (NF-κB reporter, JNK activation), in vitro immunoprecipitation binding assay, dominant-negative overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (reporter assay, kinase activation, binding assay, dominant-negative) in a single focused mechanistic study; foundational paper independently cited across many subsequent works","pmids":["9792649"],"is_preprint":false},{"year":2014,"finding":"IL-18RAP amplifies PRR-induced cytokine secretion in human macrophages by responding to NOD2-initiated early, caspase-1-dependent autocrine IL-18; this signal dramatically enhances MAPK, NF-κB, PI3K, and calcium signaling. Reconstituting MAPK activation rescues decreased cytokine output in IL-18RAP-deficient macrophages stimulated through NOD2.","method":"siRNA knockdown of IL-18RAP in primary human monocyte-derived macrophages, pathway inhibitors, cytokine ELISA, MAPK/NF-κB phosphorylation assays, rescue by constitutively active MAPK constructs","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype, pathway placement confirmed by rescue experiment, multiple signaling readouts in primary human cells","pmids":["24842757"],"is_preprint":false},{"year":2014,"finding":"The disease-risk SNP rs917997 (AA genotype) reduces cell-surface IL-18RAP protein expression in macrophages, and concurrently decreases IL-18R1 and IL-1R1 surface expression, leading to diminished PRR-, IL-18-, and IL-1β-induced MAPK and NF-κB signaling and reduced cytokine secretion.","method":"Flow cytometry for cell-surface protein quantification, cytokine ELISA, MAPK/NF-κB phosphorylation assays in primary macrophages stratified by rs917997 genotype","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in primary human cells from genotyped donors, single lab","pmids":["24842757"],"is_preprint":false},{"year":2007,"finding":"Alternative splicing of IL-18RAP mRNA produces truncated isoforms in human testicular tissue, predicted to encode proteins with altered amino acid content, suggesting a potential regulatory role on IL-18 signaling through truncated receptor variants.","method":"RT-PCR amplification of full coding sequence, cDNA sequencing to confirm splice variants, computational protein modeling","journal":"Cytokine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (RT-PCR/sequencing), no functional validation of truncated isoform activity","pmids":["17897836"],"is_preprint":false},{"year":2013,"finding":"The rs917997 G allele (associated with T1D susceptibility) is linked to higher IL-18RAP surface expression on NK cells and higher IL18RAP gene expression in activated T cells, correlating with hyperresponsiveness to IL-18 stimulation (higher IFNγ production by PBMCs treated with IL-12 and IL-18).","method":"Flow cytometry for NK cell surface IL-18RAP, gene expression analysis in activated T cells, IFNγ ELISA from PBMCs stratified by rs917997 genotype","journal":"Journal of autoimmunity","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple measurements (surface protein, gene expression, functional cytokine output) across cell types, single lab, correlative but consistent","pmids":["23891168"],"is_preprint":false},{"year":2024,"finding":"Eupafolin directly binds IL-18RAP (confirmed by biolayer interferometry) and impedes assembly of the IL-18 receptor complex, blocking IL-18-mediated NF-κB activation in cancer-associated fibroblasts, thereby reducing IL-6 synthesis and secretion and consequently inactivating STAT3 in gastric cancer cells.","method":"Biolayer interferometry (direct binding), immunoprecipitation (complex formation), NF-κB reporter/western blot, IL-6 ELISA, STAT3 phosphorylation assay, in vitro cell proliferation/spheroid assay, in vivo xenograft","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by biolayer interferometry plus functional downstream readouts in vitro and in vivo, single lab","pmids":["39265444"],"is_preprint":false},{"year":2017,"finding":"The A allele of rs7559479 in the 3′ UTR of IL18RAP increases binding of miR-136 to IL18RAP mRNA, demonstrated by luciferase reporter assay, providing a post-transcriptional mechanism of IL-18RAP expression regulation.","method":"Luciferase reporter assay with plasmids containing rs7559479 allele variants transfected into cells","journal":"BMJ open","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro functional assay (reporter) but single lab and single method with no mRNA or protein-level validation","pmids":["29146643"],"is_preprint":false}],"current_model":"IL18RAP (AcPL/CD218b) is an obligate co-receptor subunit that, together with IL-18R1, forms the functional IL-18 signaling receptor complex: IL-18R1 binds the cytokine while IL-18RAP lacks appreciable IL-18 binding affinity on its own but is essential for downstream NF-κB and JNK activation; in macrophages, IL-18RAP also amplifies NOD2-initiated innate signaling by coupling autocrine, caspase-1-dependent IL-18 to MAPK, NF-κB, PI3K, and calcium pathways, and its expression level—regulated by disease-associated SNPs and miR-136—determines the magnitude of both IL-18 and IL-1 responses; pharmacological blockade of IL-18RAP with eupafolin (a direct binder confirmed by biolayer interferometry) disrupts receptor complex assembly and NF-κB/STAT3 signaling in cancer-associated fibroblasts."},"narrative":{"mechanistic_narrative":"IL18RAP (AcPL/CD218b) is an obligate co-receptor subunit of the IL-18 signaling receptor, functioning together with IL-18R1 to transduce cytokine signals into innate and adaptive immune responses [PMID:9792649]. AcPL has no appreciable intrinsic IL-18 binding affinity, but its co-expression with IL-18R1 is non-redundantly required to activate NF-κB and JNK upon IL-18 stimulation, as a dominant-negative AcPL specifically abolishes this signaling [PMID:9792649]. Beyond the canonical receptor, IL18RAP amplifies pattern-recognition-receptor signaling in human macrophages: it couples NOD2-initiated, caspase-1-dependent autocrine IL-18 to MAPK, NF-κB, PI3K, and calcium pathways, and restoring MAPK activation rescues the cytokine deficit of IL-18RAP-deficient macrophages [PMID:24842757]. The magnitude of IL-18 (and IL-1β) responses tracks with IL-18RAP abundance, which is set by disease-associated regulatory variants and post-transcriptional control: the rs917997 genotype tunes cell-surface receptor levels and downstream signaling output [PMID:24842757, PMID:23891168], and the rs7559479 3′UTR allele modulates miR-136 binding to IL18RAP mRNA [PMID:29146643]. Pharmacological targeting of IL18RAP is feasible: eupafolin binds IL-18RAP directly and disrupts receptor complex assembly, blocking IL-18-driven NF-κB and downstream IL-6/STAT3 signaling in cancer-associated fibroblasts [PMID:39265444].","teleology":[{"year":1998,"claim":"Established that IL-18 signaling requires a second receptor subunit beyond the ligand-binding chain, defining IL18RAP as an essential, non-redundant signal-transducing co-receptor.","evidence":"Transient transfection NF-κB reporter and JNK assays, in vitro IP binding, and dominant-negative overexpression in cell lines","pmids":["9792649"],"confidence":"High","gaps":["Structural basis of the IL-18R1/IL18RAP/IL-18 ternary complex not resolved","Identity of the intracellular adaptors recruited to AcPL TIR domain not defined here","Does not address tissue-specific or quantitative regulation of the co-receptor"]},{"year":2007,"claim":"Asked whether IL18RAP output could be modulated by receptor isoform diversity, identifying truncated splice variants in testis as a candidate regulatory mechanism.","evidence":"RT-PCR amplification, cDNA sequencing, and computational protein modeling of human testicular tissue","pmids":["17897836"],"confidence":"Low","gaps":["No functional validation that truncated isoforms alter IL-18 signaling","Single method, single lab, no protein-level confirmation","Physiological role of testicular expression unexplored"]},{"year":2013,"claim":"Connected a disease-risk SNP to IL18RAP function, showing that rs917997 genotype sets receptor expression and IL-18 responsiveness in immune cells.","evidence":"Flow cytometry of NK-cell surface IL-18RAP, T-cell gene expression, and IFNγ ELISA from genotype-stratified PBMCs","pmids":["23891168"],"confidence":"Medium","gaps":["Correlative association, no direct demonstration that the SNP causally alters expression","Mechanism linking the variant to expression level not defined","Limited to specific immune cell types"]},{"year":2014,"claim":"Defined IL18RAP as an amplifier of innate PRR signaling and showed quantitatively how a risk SNP lowers receptor surface levels to blunt cytokine responses.","evidence":"siRNA knockdown, pathway inhibitors, MAPK rescue constructs, flow cytometry, and cytokine ELISA in primary human macrophages","pmids":["24842757"],"confidence":"High","gaps":["rs917997-to-expression mechanism (idx 2) is correlative across genotyped donors from a single lab","Direct interaction of IL18RAP with NOD2-pathway components not mapped","How a single co-receptor coordinately affects IL-18R1 and IL-1R1 surface levels unexplained"]},{"year":2017,"claim":"Provided a post-transcriptional mechanism for IL18RAP dosage control, showing a 3′UTR allele alters miR-136 targeting.","evidence":"Luciferase reporter assay comparing rs7559479 allele variants in transfected cells","pmids":["29146643"],"confidence":"Medium","gaps":["Single reporter assay with no endogenous mRNA or protein-level validation","Physiological contexts where miR-136 regulates IL18RAP not established","Effect on actual signaling output not measured"]},{"year":2024,"claim":"Demonstrated that IL18RAP is pharmacologically druggable, with a direct binder disrupting receptor assembly and downstream tumor-supportive signaling.","evidence":"Biolayer interferometry, IP, NF-κB reporter/western, IL-6 ELISA, STAT3 phospho-assay, spheroid assays, and xenograft for eupafolin in cancer-associated fibroblasts","pmids":["39265444"],"confidence":"Medium","gaps":["Eupafolin binding site and selectivity over IL-18R1 not mapped","Single-lab study without independent confirmation","In vivo target engagement vs off-target effects not separated"]},{"year":null,"claim":"The structural mechanism of receptor complex assembly and the precise intracellular signaling adaptors engaged by IL18RAP remain to be defined.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of the IL-18R1/IL18RAP signaling complex in the corpus","TIR-domain adaptor recruitment to AcPL not directly characterized","In vivo / genetic knockout phenotype not represented"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]}],"complexes":["IL-18 receptor complex (IL-18R1/IL18RAP)"],"partners":["IL18R1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95256","full_name":"Interleukin-18 receptor accessory protein","aliases":["Accessory protein-like","AcPL","CD218 antigen-like family member B","CDw218b","IL-1R accessory protein-like","IL-1RAcPL","Interleukin-1 receptor 7","IL-1R-7","IL-1R7","Interleukin-18 receptor accessory protein-like","Interleukin-18 receptor beta","IL-18R-beta","IL-18Rbeta"],"length_aa":599,"mass_kda":68.3,"function":"Within the IL18 receptor complex, does not mediate IL18-binding, but involved in IL18-dependent signal transduction, leading to NF-kappa-B and JNK activation (PubMed:14528293, PubMed:25500532, PubMed:9792649). May play a role in IL18-mediated IFNG synthesis from T-helper 1 (Th1) cells (Probable)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O95256/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL18RAP","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL18RAP","total_profiled":1310},"omim":[{"mim_id":"612007","title":"CELIAC DISEASE, SUSCEPTIBILITY TO, 9; CELIAC9","url":"https://www.omim.org/entry/612007"},{"mim_id":"612006","title":"CELIAC DISEASE, SUSCEPTIBILITY TO, 8; CELIAC8","url":"https://www.omim.org/entry/612006"},{"mim_id":"609888","title":"LEPROSY, SUSCEPTIBILITY TO, 1; LPRS1","url":"https://www.omim.org/entry/609888"},{"mim_id":"606001","title":"INTERLEUKIN 32; IL32","url":"https://www.omim.org/entry/606001"},{"mim_id":"604509","title":"INTERLEUKIN 18 RECEPTOR ACCESSORY PROTEIN; IL18RAP","url":"https://www.omim.org/entry/604509"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":101.8}],"url":"https://www.proteinatlas.org/search/IL18RAP"},"hgnc":{"alias_symbol":["AcPL","CD218b"],"prev_symbol":[]},"alphafold":{"accession":"O95256","domains":[{"cath_id":"2.60.40.10","chopping":"163-244","consensus_level":"medium","plddt":88.4646,"start":163,"end":244},{"cath_id":"2.60.40.10","chopping":"253-355","consensus_level":"high","plddt":93.0152,"start":253,"end":355},{"cath_id":"3.40.50.10140","chopping":"406-417_431-559","consensus_level":"high","plddt":87.9316,"start":406,"end":559},{"cath_id":"1.20.5","chopping":"359-397","consensus_level":"medium","plddt":85.0738,"start":359,"end":397}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95256","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95256-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95256-F1-predicted_aligned_error_v6.png","plddt_mean":77.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL18RAP","jax_strain_url":"https://www.jax.org/strain/search?query=IL18RAP"},"sequence":{"accession":"O95256","fasta_url":"https://rest.uniprot.org/uniprotkb/O95256.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95256/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95256"}},"corpus_meta":[{"pmid":"9792649","id":"PMC_9792649","title":"Cloning of a novel receptor subunit, AcPL, required for interleukin-18 signaling.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9792649","citation_count":273,"is_preprint":false},{"pmid":"18439550","id":"PMC_18439550","title":"Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP.","date":"2008","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18439550","citation_count":215,"is_preprint":false},{"pmid":"24842757","id":"PMC_24842757","title":"The IL18RAP region disease polymorphism decreases IL-18RAP/IL-18R1/IL-1R1 expression and signaling through innate receptor-initiated pathways.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24842757","citation_count":55,"is_preprint":false},{"pmid":"27775096","id":"PMC_27775096","title":"Genetic analysis of innate immunity in Behcet's disease identifies an association with IL-37 and IL-18RAP.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27775096","citation_count":34,"is_preprint":false},{"pmid":"19103669","id":"PMC_19103669","title":"Association study of the IL18RAP locus in three European populations with coeliac disease.","date":"2008","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19103669","citation_count":27,"is_preprint":false},{"pmid":"22550553","id":"PMC_22550553","title":"An Association Study of Interleukin 18 Receptor Genes (IL18R1 and IL18RAP) in Lumbar Disc Degeneration.","date":"2012","source":"The open orthopaedics journal","url":"https://pubmed.ncbi.nlm.nih.gov/22550553","citation_count":22,"is_preprint":false},{"pmid":"23891168","id":"PMC_23891168","title":"The autoimmune disease-associated SNP rs917997 of IL18RAP controls IFNγ production by PBMC.","date":"2013","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/23891168","citation_count":22,"is_preprint":false},{"pmid":"17897836","id":"PMC_17897836","title":"Identification of IL-18RAP mRNA truncated splice variants in human testis and the other human tissues.","date":"2007","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/17897836","citation_count":19,"is_preprint":false},{"pmid":"26566691","id":"PMC_26566691","title":"Polymorphisms of ST2-IL18R1-IL18RAP gene cluster: a new risk for autoimmune thyroid diseases.","date":"2015","source":"International journal of immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/26566691","citation_count":14,"is_preprint":false},{"pmid":"19473509","id":"PMC_19473509","title":"Lack of association between polymorphisms of the IL18R1 and IL18RAP genes and cardiovascular risk: the MORGAM Project.","date":"2009","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19473509","citation_count":13,"is_preprint":false},{"pmid":"29146643","id":"PMC_29146643","title":"Are IL18RAP gene polymorphisms associated with body mass regulation? A cross-sectional study.","date":"2017","source":"BMJ open","url":"https://pubmed.ncbi.nlm.nih.gov/29146643","citation_count":10,"is_preprint":false},{"pmid":"39265444","id":"PMC_39265444","title":"Eupafolin hinders cross-talk between gastric cancer cells and cancer-associated fibroblasts by abrogating the IL18/IL18RAP signaling axis.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39265444","citation_count":6,"is_preprint":false},{"pmid":"26289103","id":"PMC_26289103","title":"Systematic review and meta-analysis of the association between IL18RAP rs917997 and CCR3 rs6441961 polymorphisms with celiac disease risks.","date":"2015","source":"Expert review of gastroenterology & hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/26289103","citation_count":4,"is_preprint":false},{"pmid":"31126849","id":"PMC_31126849","title":"Role of APOE and IL18RAP gene polymorphisms in cervical spondylotic myelopathy in Indian population.","date":"2019","source":"Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia","url":"https://pubmed.ncbi.nlm.nih.gov/31126849","citation_count":3,"is_preprint":false},{"pmid":"31147177","id":"PMC_31147177","title":"IL18RAP polymorphisms and its plasma levels in patients with Lumbar disc degeneration.","date":"2019","source":"Clinical neurology and neurosurgery","url":"https://pubmed.ncbi.nlm.nih.gov/31147177","citation_count":2,"is_preprint":false},{"pmid":"40124360","id":"PMC_40124360","title":"Immune and vascular modulation by HERVs: the role of CXCR1 and IL18RAP in dengue severity progression.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40124360","citation_count":1,"is_preprint":false},{"pmid":"29285382","id":"PMC_29285382","title":"IL18 rs360719 A>G, IL18R1 rs13015714 G>T, IL18RAP rs917997 C>T and IL28B rs8099917 T>G polymorphisms and risk of gastric cardiac adenocarcinoma.","date":"2017","source":"Molecular and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29285382","citation_count":1,"is_preprint":false},{"pmid":"24909718","id":"PMC_24909718","title":"Analysis of the association of polymorphic loci rs917997 in IL18RAP gene and rs187238 in IL18 gene with the risk for non-Hodgkin's malignant lymphomas in Novosibirsk population.","date":"2014","source":"Bulletin of experimental biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24909718","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.19.25336165","title":"Biobank-scale Bayesian TWAS reveals splicing-mediated mechanisms of complex disease","date":"2025-09-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.19.25336165","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.09.658549","title":"Identification of reactive CpGs and RNA expression in early COVID-19 through  <i>cis</i>  -eQTM analysis reflecting disease severity and recovery","date":"2025-06-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.09.658549","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12417,"output_tokens":1952,"usd":0.033266,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8936,"output_tokens":2644,"usd":0.05539,"stage2_stop_reason":"end_turn"},"total_usd":0.088656,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"IL18RAP (AcPL) is a required co-receptor subunit for IL-18 signaling: both IL-1R-rp1 (IL-18R1) and AcPL must be co-expressed to induce NF-κB activity and activate JNK in response to IL-18. AcPL alone cannot bind IL-18 with appreciable affinity; a dominant-negative AcPL specifically inhibits IL-18 signaling, establishing its non-redundant role in signal transduction.\",\n      \"method\": \"Transient transfection assays (NF-κB reporter, JNK activation), in vitro immunoprecipitation binding assay, dominant-negative overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (reporter assay, kinase activation, binding assay, dominant-negative) in a single focused mechanistic study; foundational paper independently cited across many subsequent works\",\n      \"pmids\": [\"9792649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-18RAP amplifies PRR-induced cytokine secretion in human macrophages by responding to NOD2-initiated early, caspase-1-dependent autocrine IL-18; this signal dramatically enhances MAPK, NF-κB, PI3K, and calcium signaling. Reconstituting MAPK activation rescues decreased cytokine output in IL-18RAP-deficient macrophages stimulated through NOD2.\",\n      \"method\": \"siRNA knockdown of IL-18RAP in primary human monocyte-derived macrophages, pathway inhibitors, cytokine ELISA, MAPK/NF-κB phosphorylation assays, rescue by constitutively active MAPK constructs\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype, pathway placement confirmed by rescue experiment, multiple signaling readouts in primary human cells\",\n      \"pmids\": [\"24842757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The disease-risk SNP rs917997 (AA genotype) reduces cell-surface IL-18RAP protein expression in macrophages, and concurrently decreases IL-18R1 and IL-1R1 surface expression, leading to diminished PRR-, IL-18-, and IL-1β-induced MAPK and NF-κB signaling and reduced cytokine secretion.\",\n      \"method\": \"Flow cytometry for cell-surface protein quantification, cytokine ELISA, MAPK/NF-κB phosphorylation assays in primary macrophages stratified by rs917997 genotype\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in primary human cells from genotyped donors, single lab\",\n      \"pmids\": [\"24842757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Alternative splicing of IL-18RAP mRNA produces truncated isoforms in human testicular tissue, predicted to encode proteins with altered amino acid content, suggesting a potential regulatory role on IL-18 signaling through truncated receptor variants.\",\n      \"method\": \"RT-PCR amplification of full coding sequence, cDNA sequencing to confirm splice variants, computational protein modeling\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (RT-PCR/sequencing), no functional validation of truncated isoform activity\",\n      \"pmids\": [\"17897836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The rs917997 G allele (associated with T1D susceptibility) is linked to higher IL-18RAP surface expression on NK cells and higher IL18RAP gene expression in activated T cells, correlating with hyperresponsiveness to IL-18 stimulation (higher IFNγ production by PBMCs treated with IL-12 and IL-18).\",\n      \"method\": \"Flow cytometry for NK cell surface IL-18RAP, gene expression analysis in activated T cells, IFNγ ELISA from PBMCs stratified by rs917997 genotype\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple measurements (surface protein, gene expression, functional cytokine output) across cell types, single lab, correlative but consistent\",\n      \"pmids\": [\"23891168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Eupafolin directly binds IL-18RAP (confirmed by biolayer interferometry) and impedes assembly of the IL-18 receptor complex, blocking IL-18-mediated NF-κB activation in cancer-associated fibroblasts, thereby reducing IL-6 synthesis and secretion and consequently inactivating STAT3 in gastric cancer cells.\",\n      \"method\": \"Biolayer interferometry (direct binding), immunoprecipitation (complex formation), NF-κB reporter/western blot, IL-6 ELISA, STAT3 phosphorylation assay, in vitro cell proliferation/spheroid assay, in vivo xenograft\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by biolayer interferometry plus functional downstream readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"39265444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The A allele of rs7559479 in the 3′ UTR of IL18RAP increases binding of miR-136 to IL18RAP mRNA, demonstrated by luciferase reporter assay, providing a post-transcriptional mechanism of IL-18RAP expression regulation.\",\n      \"method\": \"Luciferase reporter assay with plasmids containing rs7559479 allele variants transfected into cells\",\n      \"journal\": \"BMJ open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro functional assay (reporter) but single lab and single method with no mRNA or protein-level validation\",\n      \"pmids\": [\"29146643\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL18RAP (AcPL/CD218b) is an obligate co-receptor subunit that, together with IL-18R1, forms the functional IL-18 signaling receptor complex: IL-18R1 binds the cytokine while IL-18RAP lacks appreciable IL-18 binding affinity on its own but is essential for downstream NF-κB and JNK activation; in macrophages, IL-18RAP also amplifies NOD2-initiated innate signaling by coupling autocrine, caspase-1-dependent IL-18 to MAPK, NF-κB, PI3K, and calcium pathways, and its expression level—regulated by disease-associated SNPs and miR-136—determines the magnitude of both IL-18 and IL-1 responses; pharmacological blockade of IL-18RAP with eupafolin (a direct binder confirmed by biolayer interferometry) disrupts receptor complex assembly and NF-κB/STAT3 signaling in cancer-associated fibroblasts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL18RAP (AcPL/CD218b) is an obligate co-receptor subunit of the IL-18 signaling receptor, functioning together with IL-18R1 to transduce cytokine signals into innate and adaptive immune responses [#0]. AcPL has no appreciable intrinsic IL-18 binding affinity, but its co-expression with IL-18R1 is non-redundantly required to activate NF-\\u03baB and JNK upon IL-18 stimulation, as a dominant-negative AcPL specifically abolishes this signaling [#0]. Beyond the canonical receptor, IL18RAP amplifies pattern-recognition-receptor signaling in human macrophages: it couples NOD2-initiated, caspase-1-dependent autocrine IL-18 to MAPK, NF-\\u03baB, PI3K, and calcium pathways, and restoring MAPK activation rescues the cytokine deficit of IL-18RAP-deficient macrophages [#1]. The magnitude of IL-18 (and IL-1\\u03b2) responses tracks with IL-18RAP abundance, which is set by disease-associated regulatory variants and post-transcriptional control: the rs917997 genotype tunes cell-surface receptor levels and downstream signaling output [#2, #4], and the rs7559479 3\\u2032UTR allele modulates miR-136 binding to IL18RAP mRNA [#6]. Pharmacological targeting of IL18RAP is feasible: eupafolin binds IL-18RAP directly and disrupts receptor complex assembly, blocking IL-18-driven NF-\\u03baB and downstream IL-6/STAT3 signaling in cancer-associated fibroblasts [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that IL-18 signaling requires a second receptor subunit beyond the ligand-binding chain, defining IL18RAP as an essential, non-redundant signal-transducing co-receptor.\",\n      \"evidence\": \"Transient transfection NF-\\u03baB reporter and JNK assays, in vitro IP binding, and dominant-negative overexpression in cell lines\",\n      \"pmids\": [\"9792649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the IL-18R1/IL18RAP/IL-18 ternary complex not resolved\",\n        \"Identity of the intracellular adaptors recruited to AcPL TIR domain not defined here\",\n        \"Does not address tissue-specific or quantitative regulation of the co-receptor\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Asked whether IL18RAP output could be modulated by receptor isoform diversity, identifying truncated splice variants in testis as a candidate regulatory mechanism.\",\n      \"evidence\": \"RT-PCR amplification, cDNA sequencing, and computational protein modeling of human testicular tissue\",\n      \"pmids\": [\"17897836\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No functional validation that truncated isoforms alter IL-18 signaling\",\n        \"Single method, single lab, no protein-level confirmation\",\n        \"Physiological role of testicular expression unexplored\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected a disease-risk SNP to IL18RAP function, showing that rs917997 genotype sets receptor expression and IL-18 responsiveness in immune cells.\",\n      \"evidence\": \"Flow cytometry of NK-cell surface IL-18RAP, T-cell gene expression, and IFN\\u03b3 ELISA from genotype-stratified PBMCs\",\n      \"pmids\": [\"23891168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Correlative association, no direct demonstration that the SNP causally alters expression\",\n        \"Mechanism linking the variant to expression level not defined\",\n        \"Limited to specific immune cell types\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined IL18RAP as an amplifier of innate PRR signaling and showed quantitatively how a risk SNP lowers receptor surface levels to blunt cytokine responses.\",\n      \"evidence\": \"siRNA knockdown, pathway inhibitors, MAPK rescue constructs, flow cytometry, and cytokine ELISA in primary human macrophages\",\n      \"pmids\": [\"24842757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"rs917997-to-expression mechanism (idx 2) is correlative across genotyped donors from a single lab\",\n        \"Direct interaction of IL18RAP with NOD2-pathway components not mapped\",\n        \"How a single co-receptor coordinately affects IL-18R1 and IL-1R1 surface levels unexplained\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided a post-transcriptional mechanism for IL18RAP dosage control, showing a 3\\u2032UTR allele alters miR-136 targeting.\",\n      \"evidence\": \"Luciferase reporter assay comparing rs7559479 allele variants in transfected cells\",\n      \"pmids\": [\"29146643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single reporter assay with no endogenous mRNA or protein-level validation\",\n        \"Physiological contexts where miR-136 regulates IL18RAP not established\",\n        \"Effect on actual signaling output not measured\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that IL18RAP is pharmacologically druggable, with a direct binder disrupting receptor assembly and downstream tumor-supportive signaling.\",\n      \"evidence\": \"Biolayer interferometry, IP, NF-\\u03baB reporter/western, IL-6 ELISA, STAT3 phospho-assay, spheroid assays, and xenograft for eupafolin in cancer-associated fibroblasts\",\n      \"pmids\": [\"39265444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Eupafolin binding site and selectivity over IL-18R1 not mapped\",\n        \"Single-lab study without independent confirmation\",\n        \"In vivo target engagement vs off-target effects not separated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural mechanism of receptor complex assembly and the precise intracellular signaling adaptors engaged by IL18RAP remain to be defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of the IL-18R1/IL18RAP signaling complex in the corpus\",\n        \"TIR-domain adaptor recruitment to AcPL not directly characterized\",\n        \"In vivo / genetic knockout phenotype not represented\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"IL-18 receptor complex (IL-18R1/IL18RAP)\"],\n    \"partners\": [\"IL18R1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}