{"gene":"IL18BP","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1999,"finding":"IL-18BP was originally discovered by subjecting concentrated human urine to an IL-18 ligand affinity column, purifying a novel 40 amino acid polypeptide. Complete ORF isolation from cDNA libraries revealed a unique soluble antagonist sharing homology with viral proteins, distinct from IL-18Rα and IL-18Rβ chains. It forms a 1:1 high-affinity complex with IL-18 (Kd=400 pM) with a very low dissociation rate.","method":"IL-18 ligand affinity chromatography, protein microsequencing, cDNA library screening, in vitro binding/neutralization assays","journal":"Immune network","confidence":"High","confidence_rationale":"Tier 1 / Strong — original biochemical purification, protein sequencing, and functional reconstitution; replicated across multiple subsequent studies confirming the Kd","pmids":["38455460","11497494"],"is_preprint":false},{"year":2001,"finding":"IL-18BP (isoform a) forms a 1:1 stoichiometric high-affinity complex with IL-18 (Kd=400 pM) with a very low dissociation rate, effectively blocking IL-18 bioactivity. A sandwich ELISA specific to IL-18BPa was developed and validated, showing no cross-reactivity with IL-18 or other IL-18BP isoforms (b, c, d). Using mass-action calculations, most circulating IL-18 in healthy individuals (~85%) is free, whereas in sepsis, the majority is bound to IL-18BPa.","method":"Sandwich ELISA, electrochemiluminescence assay, mass-action law calculations","journal":"Cytokine","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding characterization with quantitative affinity measurement replicated across multiple studies","pmids":["11497494"],"is_preprint":false},{"year":2008,"finding":"IFN-γ induces IL-18BP expression in DLD-1 colon carcinoma cells via direct binding of STAT1 to a proximal gamma-activated sequence (GAS) element in the IL-18BP promoter. Mutational analysis showed this proximal GAS is pivotal; siRNA knockdown confirmed essential role of STAT1; EMSA and chromatin immunoprecipitation (ChIP) proved STAT1 binding to this specific GAS site. Maximal expression required de novo protein synthesis but was independent of IRF-1.","method":"Promoter mutational analysis, siRNA knockdown, EMSA, chromatin immunoprecipitation (ChIP)","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods (mutagenesis, siRNA, EMSA, ChIP) in a single study establishing the STAT1/GAS transcriptional mechanism","pmids":["19046253"],"is_preprint":false},{"year":2018,"finding":"Remifentanil upregulates hepatic IL-18BP expression at the transcriptional level via activation of STAT1 and C/EBPβ transcription factors. Actinomycin D abolished remifentanil-induced IL-18BP mRNA upregulation; luciferase reporter assay confirmed increased IL-18BP promoter transcription; Western blot and ChIP assays showed STAT1 and C/EBPβ activation and binding; silencing of either STAT1 or C/EBPβ blocked IL-18BP upregulation. The induced IL-18BP was functionally active, inhibiting IL-18-activated NF-κB phosphorylation.","method":"Actinomycin D inhibition, luciferase reporter assay, ChIP, Western blot, siRNA knockdown","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods (reporter assay, ChIP, siRNA, functional NF-κB readout) in single study","pmids":["30089853"],"is_preprint":false},{"year":2018,"finding":"Epigenetic regulation by CpG methylation at a specific CpG site (CpG2) neighboring the γ-activated sequence (GAS) in the IL18BP promoter determines differential IFNγ-induced IL-18BP expression between monocytic and epithelial cells. CpG2 is constitutively methylated in monocytic but unmethylated in epithelial cells. 5-aza-2'-deoxycytidine (DNA demethylation) enhanced IFNγ-induced IL-18BP only in monocytic cells; demethylation impeded MeCP2 binding to CpG2, increased adjacent H3K9-acetylation, and enhanced RNA-polymerase-II recruitment to the IL18BP transcriptional start.","method":"5-aza-2'-deoxycytidine treatment, ChIP for MeCP2 and histone modifications, RNA-polymerase-II recruitment analysis, promoter CpG methylation analysis","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal epigenetic methods (ChIP, demethylation treatment, histone modification analysis) in a single study","pmids":["29409936"],"is_preprint":false},{"year":2019,"finding":"Inherited homozygous loss-of-function deletion in IL18BP causes IL-18BP deficiency in humans. In the absence of IL-18BP, excessive NK cell activation by IL-18 results in uncontrolled killing of human hepatocytes in vitro. Human IL-18 and IL-18BP are both secreted primarily by hepatocytes and macrophages in the liver. This establishes IL-18BP as an essential restraint on IL-18-driven NK cell cytotoxicity in the liver.","method":"Human genetic analysis (homozygous deletion), in vitro NK cell cytotoxicity assay with human hepatocytes, IL-18BP knockout functional studies","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — human genetic loss-of-function combined with direct in vitro functional rescue/cytotoxicity assay","pmids":["31213488"],"is_preprint":false},{"year":2020,"finding":"IL-18BP is a high-affinity decoy receptor that is frequently upregulated in diverse human and mouse tumors and limits anti-tumor activity of IL-18 in vivo. Directed evolution was used to engineer 'decoy-resistant' IL-18 (DR-18) that maintains receptor signaling but is impervious to IL-18BP inhibition, demonstrating that the IL-18BP:IL-18 interaction is the mechanistic barrier to IL-18 anti-tumor efficacy.","method":"Directed evolution/protein engineering, mouse tumor models, flow cytometry for T cell phenotyping","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — engineering approach with in vivo functional validation across multiple tumor models, demonstrating IL-18BP as the mechanistic barrier","pmids":["32581358"],"is_preprint":false},{"year":2007,"finding":"In human monocytic THP-1 cells stimulated with P. gingivalis LPS, both IL-18 and IL-18BPa are secreted. Addition of antibodies to IL-18BPa to stimulated cultures resulted in increased levels of free IL-18, directly demonstrating a specific neutralizing interaction between IL-18 and IL-18BPa in this cellular system. VIP (10⁻⁸M) inhibited both IL-18 and IL-18BPa secretion.","method":"ELISA, neutralizing antibody competition assay in THP-1 cell cultures","journal":"Journal of dental research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — antibody competition demonstrates functional IL-18:IL-18BPa interaction in cellular context, single lab with two methods","pmids":["17720860"],"is_preprint":false},{"year":2003,"finding":"IL-18BPa:Fc significantly inhibited LPS/IL-12-induced IFN-γ and MMP-9 release from human whole blood cultures, demonstrating functional IL-18 blockade in a physiologically relevant ex vivo system. IL-18BPa:Fc cooperated additively with immunosuppressive drugs (dexamethasone, mycophenolic acid) to further reduce IFN-γ production.","method":"Human whole blood ex vivo culture, ELISA for IFN-γ and MMP-9","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean functional assay in primary human whole blood with defined readouts, single lab","pmids":["12907250"],"is_preprint":false},{"year":2003,"finding":"A mouse monoclonal antibody (2A6H11) specific for rat IL-18BP was generated. Its binding epitope was mapped to amino acids 29-60 on IL-18BP. Critically, this antibody does not interfere with IL-18BP function (i.e., does not block IL-18 binding).","method":"Monoclonal antibody generation, epitope mapping, functional ELISA","journal":"Immunology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct epitope mapping and functional characterization of antibody binding site, single lab","pmids":["12505199"],"is_preprint":false},{"year":2003,"finding":"LPS treatment of rats selectively upregulates IL-18BP mRNA in the liver (~12-fold above naive levels, peaking at 3h), whereas IL-18 mRNA expression in the liver was unaffected by LPS. This differential regulation suggests an endogenous feedback mechanism for controlling IL-18 activity during inflammatory responses.","method":"Real-time PCR of rat liver tissue after peripheral LPS injection","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single in vivo experiment with quantitative PCR, single lab","pmids":["12788303"],"is_preprint":false},{"year":2016,"finding":"Bioinformatics analysis across 86 mammalian species shows IL-18BP is consistently most similar to IL-1R9 (IL-1R accessory protein-like 2). IL-1R9 and IL-1R8 share conserved amino acid sequences homologous to binding site A of human and viral IL-18BPs, conserved intron/exon boundaries, and protein structure, suggesting evolutionary relationship and potential IL-18 binding capacity.","method":"Bioinformatics/phylogenetic analysis of Ensembl and NCBI databases, protein structure comparison","journal":"Journal of immunology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/bioinformatics only, no experimental validation of IL-1R9 binding IL-18","pmids":["27881706"],"is_preprint":false},{"year":2023,"finding":"MD simulation analysis of all known IL-18–IL-18BP PDB crystal structures revealed that residues 68–81 of IL-18 adopt a disordered conformation in all IL-18–IL-18BP complexes but a 310-helical structure in IL-18–receptor complexes. C74 within this epitope can form an intermolecular disulfide bond in the human tetrameric IL-18–IL-18BP assembly. Simulations show the helical form of this epitope stabilizes the heterodimer by reducing backbone flexibility, and the exposed C74 sidechain in disordered form mediates self-assembly of IL-18–IL-18BP dimers.","method":"All-atom molecular dynamics simulations of PDB structures and computed models","journal":"Computational and structural biotechnology journal","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational only (MD simulations), no experimental validation of the proposed disulfide or helical state","pmids":["37484491"],"is_preprint":false},{"year":2022,"finding":"In rainbow trout, recombinant IL-18BP (rIL-18BP) significantly downregulates NF-κB activity induced by IL-18 via its receptor complex (IL-18Rα + IL-18Rβ) in HEK293T cells, demonstrating conserved decoy receptor function. Co-IP assays showed IL-18Rβ forms a complex with MyD88, IRAK4, IRAK1, TRAF6, and TAB2, indicating IL-18Rβ is the signaling-competent subunit recruiting these downstream molecules.","method":"NF-κB reporter assay in HEK293T cells with chimeric receptor transfection, Co-immunoprecipitation","journal":"Developmental and comparative immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and functional reporter assay in a fish ortholog study, single lab","pmids":["36496012"],"is_preprint":false},{"year":2023,"finding":"In Toxoplasma gondii infection, IFN-γ produced during infection induces high levels of IL-18BP, which restrains IL-18-mediated ILC and T cell responses. Antagonism of IL-18BP with a 'decoy-to-the-decoy' (D2D) construct (non-signaling IL-18 that sequesters IL-18BP) enhanced innate lymphoid cell and T cell responses and improved parasite control, establishing IL-18BP as a functional brake on IL-18 activity in vivo. DR-18 (IL-18 resistant to IL-18BP) promoted CD4+ T cell IFN-γ but also caused CD4+ T cell-mediated pathology.","method":"Mouse infection model with T. gondii, D2D and DR-18 protein treatment, flow cytometry for immune cell responses","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo functional epistasis with engineered IL-18BP antagonist and decoy-resistant IL-18, multiple readouts","pmids":["36827187"],"is_preprint":false},{"year":2024,"finding":"An anti-IL-18BP monoclonal antibody (COM503) was generated that blocks the IL-18BP:IL-18 interaction and displaces pre-complexed IL-18 from IL-18BP, thereby restoring free IL-18 activity and enhancing T and NK cell activation in vitro. In vivo, a surrogate anti-IL-18BP antibody caused pronounced tumor microenvironment-localized immune modulation (increased polyfunctional non-exhausted T and NK cells) without systemic inflammatory cytokine elevation, establishing IL-18BP blockade as a mechanism for TME-specific IL-18 release.","method":"Anti-IL-18BP antibody generation, in vitro displacement/neutralization assay, mouse tumor models, cytokine measurement in serum vs. TME","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional in vitro displacement assay combined with in vivo tumor model with mechanistic readouts, single lab with multiple orthogonal methods","pmids":["38592331"],"is_preprint":false},{"year":2019,"finding":"miR-92b-5p directly suppresses IL-18BP expression in microglia. Transfection of miR-92b-5p into activated microglia significantly decreased IL-18BP expression while increasing IL-18 mRNA; miR-92b-5p inhibitor reversed this effect. After spinal cord injury, miR-92b-5p is upregulated in the injured cord, correlating with decreased IL-18BP and increased IL-18 expression.","method":"miRNA transfection in primary microglia, qRT-PCR, intrathecal injection of miR-92b-5p inhibitor in mouse SCI model","journal":"European review for medical and pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct miRNA manipulation with reciprocal expression changes, confirmed in vitro and in vivo, single lab","pmids":["30915731"],"is_preprint":false},{"year":2025,"finding":"In an IL-18bp knockout mouse model, excess IL-18 activity (without IL-18BP restraint) caused NK cells to be inert/hypofunctional upon mousepox infection despite being hyperactivated at rest. IL-18bp KO mice succumbed to viremic MAS-like disease with poor virus-specific CTL expansion, establishing that IL-18BP is required to maintain NK cell responsiveness to infectious challenge by preventing IL-18-driven NK hypoactivation.","method":"Il18bp knockout mouse model, mousepox infection challenge, NK cell transfer rescue experiments, flow cytometry, viral clearance assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO with defined phenotypic readout and NK rescue experiment, but preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.07.04.663237"],"is_preprint":true}],"current_model":"IL-18BP is a secreted high-affinity soluble decoy receptor (Kd ~400 pM, very slow off-rate) that neutralizes IL-18 by forming a 1:1 non-signaling complex, thereby blocking IL-18 from engaging its signaling receptors IL-18Rα/IL-18Rβ; its expression is transcriptionally induced by IFN-γ via direct STAT1 binding to a proximal GAS element in its promoter—a process epigenetically gated by CpG methylation in monocytes but not epithelial cells—creating a negative feedback loop, and its constitutive and induced secretion by hepatocytes and macrophages is essential in vivo for restraining IL-18-driven NK cell cytotoxicity against hepatocytes and for preventing pathological hyperinflammation in multiple disease contexts."},"narrative":{"mechanistic_narrative":"IL-18BP is a secreted high-affinity decoy receptor that neutralizes the pro-inflammatory cytokine IL-18, serving as a key brake on IL-18-driven immune activation [PMID:38455460, PMID:11497494, PMID:31213488]. Originally purified from human urine as a 40-residue soluble antagonist distinct from the IL-18Rα/β signaling chains, it forms a 1:1 stoichiometric complex with IL-18 (Kd ~400 pM) with a very slow dissociation rate, sequestering the cytokine and blocking its engagement of the signaling receptor and downstream NF-κB activation [PMID:38455460, PMID:11497494, PMID:30089853]. By mass-action, this binding determines the free IL-18 pool: most circulating IL-18 is free in health but largely bound in sepsis [PMID:11497494]. IL-18BP expression is transcriptionally induced by IFN-γ through direct STAT1 binding to a proximal GAS element in its promoter, constituting a negative feedback loop, and is co-regulated by C/EBPβ in hepatocytes; this induction is epigenetically gated by CpG methylation adjacent to the GAS element, which restricts IFN-γ responsiveness in monocytes relative to epithelial cells [PMID:19046253, PMID:30089853, PMID:29409936]. In vivo, IL-18BP secreted by hepatocytes and macrophages restrains IL-18-driven NK cell cytotoxicity against hepatocytes, and inherited homozygous loss-of-function deletion causes human IL-18BP deficiency with uncontrolled NK-mediated hepatocyte killing [PMID:31213488]. The same neutralizing axis acts as a barrier to IL-18 anti-tumor activity and an immune brake during infection: tumors upregulate IL-18BP to limit IL-18 efficacy, and engineered decoy-resistant IL-18 or anti-IL-18BP antibodies that displace pre-bound IL-18 restore T and NK cell activation [PMID:32581358, PMID:36827187, PMID:38592331].","teleology":[{"year":1999,"claim":"Established the existence of a soluble, secreted IL-18 antagonist distinct from the membrane IL-18 receptor chains, defining a new mode of IL-18 regulation.","evidence":"IL-18 ligand affinity chromatography from human urine, protein microsequencing, cDNA cloning, and in vitro binding/neutralization","pmids":["38455460","11497494"],"confidence":"High","gaps":["Did not resolve in vivo physiological role","Homology to viral proteins noted but structural basis of binding undefined"]},{"year":2001,"claim":"Quantified the IL-18BPa:IL-18 interaction and showed that decoy occupancy controls the free IL-18 pool, distinguishing health from sepsis.","evidence":"Isoform-specific sandwich ELISA, electrochemiluminescence, and mass-action calculations of free vs. bound IL-18","pmids":["11497494"],"confidence":"High","gaps":["Functional role of other isoforms (b, c, d) not established","Did not address tissue source of circulating IL-18BP"]},{"year":2008,"claim":"Defined the transcriptional mechanism of IL-18BP induction, showing IFN-γ drives expression via direct STAT1 binding to a proximal GAS element, formalizing a negative feedback loop.","evidence":"Promoter mutagenesis, siRNA knockdown, EMSA, and ChIP in DLD-1 colon carcinoma cells","pmids":["19046253"],"confidence":"High","gaps":["IRF-1 independence noted but identity of the required de novo synthesized protein unknown","Cell-type generality of GAS dependence not addressed in this study"]},{"year":2018,"claim":"Showed expression is epigenetically gated and co-regulated by additional factors, explaining cell-type-specific IFN-γ responsiveness.","evidence":"CpG methylation/demethylation (5-aza), MeCP2 and histone ChIP, RNA-Pol II recruitment (monocytic vs. epithelial); plus STAT1/C/EBPβ reporter, ChIP, and siRNA in hepatic cells","pmids":["29409936","30089853"],"confidence":"High","gaps":["Mechanism setting differential CpG2 methylation between lineages unknown","Interplay of C/EBPβ and STAT1 at the promoter not structurally resolved"]},{"year":2019,"claim":"Established IL-18BP as a physiologically essential restraint on IL-18, with human loss-of-function causing uncontrolled NK-mediated hepatocyte killing.","evidence":"Human homozygous deletion genetics and in vitro NK cytotoxicity assays against human hepatocytes","pmids":["31213488"],"confidence":"High","gaps":["Did not establish full spectrum of human disease phenotype","Relative contribution of hepatocyte vs. macrophage IL-18BP sources not partitioned"]},{"year":2020,"claim":"Demonstrated that the IL-18BP:IL-18 interaction is the mechanistic barrier limiting IL-18 anti-tumor activity, enabling therapeutic decoy-resistant IL-18.","evidence":"Directed evolution of decoy-resistant IL-18 (DR-18) and mouse tumor models with T cell phenotyping","pmids":["32581358"],"confidence":"High","gaps":["Drivers of tumor IL-18BP upregulation not fully defined","Did not address normal-tissue toxicity of bypassing the decoy"]},{"year":2023,"claim":"Confirmed IL-18BP as an in vivo functional brake on infection-driven lymphoid responses, with engineered antagonists revealing the protective-versus-pathological balance of unleashing IL-18.","evidence":"Mouse T. gondii infection with D2D (decoy-to-the-decoy) and DR-18 treatment, flow cytometry, parasite control readouts","pmids":["36827187"],"confidence":"High","gaps":["Threshold separating beneficial IL-18 release from CD4 T-cell pathology undefined","Generalizability across pathogens not established"]},{"year":2024,"claim":"Validated pharmacological IL-18BP blockade by antibody that displaces pre-bound IL-18, achieving tumor-localized immune activation without systemic inflammation.","evidence":"Anti-IL-18BP antibody (COM503) in vitro displacement/neutralization and mouse tumor models comparing serum vs. TME cytokines","pmids":["38592331"],"confidence":"High","gaps":["Basis of TME-restricted versus systemic effect not mechanistically resolved","Durability and resistance to blockade not addressed"]},{"year":2025,"claim":"Revealed that loss of IL-18BP restraint paradoxically renders NK cells hypofunctional during infection, framing IL-18BP as required to preserve NK responsiveness.","evidence":"Il18bp knockout mouse, mousepox challenge, NK transfer rescue, viral clearance assays (preprint)","pmids":["bio_10.1101_2025.07.04.663237"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Molecular basis of IL-18-driven NK exhaustion/hypoactivation undefined"]},{"year":null,"claim":"How IL-18BP structurally engages IL-18 to occlude receptor binding, and how higher-order self-assembly contributes to neutralization in vivo, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["Proposed C74 disulfide-mediated tetramer assembly is computational only and unvalidated experimentally","No experimental structure of the human IL-18BP self-assembled state confirmed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,6,15]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,5,7]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,6,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,3,4]}],"complexes":[],"partners":["IL18"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95998","full_name":"Interleukin-18-binding protein","aliases":["Tadekinig-alfa"],"length_aa":194,"mass_kda":21.1,"function":"Isoform A binds to IL-18 and inhibits its activity. Functions as an inhibitor of the early TH1 cytokine response","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/O95998/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL18BP","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL18BP","total_profiled":1310},"omim":[{"mim_id":"618549","title":"HEPATITIS, FULMINANT VIRAL, SUSCEPTIBILITY TO; FVH","url":"https://www.omim.org/entry/618549"},{"mim_id":"604494","title":"INTERLEUKIN 18 RECEPTOR 1; IL18R1","url":"https://www.omim.org/entry/604494"},{"mim_id":"604113","title":"INTERLEUKIN 18-BINDING PROTEIN; IL18BP","url":"https://www.omim.org/entry/604113"},{"mim_id":"600953","title":"INTERLEUKIN 18; IL18","url":"https://www.omim.org/entry/600953"},{"mim_id":"266600","title":"INFLAMMATORY BOWEL DISEASE (CROHN DISEASE) 1; IBD1","url":"https://www.omim.org/entry/266600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":44.3}],"url":"https://www.proteinatlas.org/search/IL18BP"},"hgnc":{"alias_symbol":["IL18BPa"],"prev_symbol":[]},"alphafold":{"accession":"O95998","domains":[{"cath_id":"2.60.40.10","chopping":"62-173","consensus_level":"medium","plddt":94.7405,"start":62,"end":173}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95998","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95998-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95998-F1-predicted_aligned_error_v6.png","plddt_mean":79.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL18BP","jax_strain_url":"https://www.jax.org/strain/search?query=IL18BP"},"sequence":{"accession":"O95998","fasta_url":"https://rest.uniprot.org/uniprotkb/O95998.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95998/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95998"}},"corpus_meta":[{"pmid":"32581358","id":"PMC_32581358","title":"IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32581358","citation_count":300,"is_preprint":false},{"pmid":"29472362","id":"PMC_29472362","title":"Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still's disease.","date":"2018","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/29472362","citation_count":235,"is_preprint":false},{"pmid":"11497494","id":"PMC_11497494","title":"A novel IL-18BP ELISA shows elevated serum IL-18BP in sepsis and extensive decrease of free IL-18.","date":"2001","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/11497494","citation_count":223,"is_preprint":false},{"pmid":"25548255","id":"PMC_25548255","title":"Context-dependent role of IL-18 in cancer biology and counter-regulation by IL-18BP.","date":"2014","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/25548255","citation_count":145,"is_preprint":false},{"pmid":"31213488","id":"PMC_31213488","title":"Inherited IL-18BP deficiency in human fulminant viral hepatitis.","date":"2019","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31213488","citation_count":93,"is_preprint":false},{"pmid":"24733959","id":"PMC_24733959","title":"Elevated plasma IL-37, IL-18, and IL-18BP concentrations in patients with acute coronary syndrome.","date":"2014","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/24733959","citation_count":88,"is_preprint":false},{"pmid":"20121409","id":"PMC_20121409","title":"Serum IL-18 and IL-18BP levels in patients with Chikungunya virus infection.","date":"2010","source":"Viral immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20121409","citation_count":48,"is_preprint":false},{"pmid":"19225717","id":"PMC_19225717","title":"Expression of interleukin-18, IL-18BP, and IL-18R in serum, synovial fluid, and synovial tissue in patients with rheumatoid arthritis.","date":"2009","source":"Clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19225717","citation_count":43,"is_preprint":false},{"pmid":"25108227","id":"PMC_25108227","title":"Pressure overload induces IL-18 and IL-18R expression, but markedly suppresses IL-18BP expression in a rabbit model. IL-18 potentiates TNF-α-induced cardiomyocyte death.","date":"2014","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/25108227","citation_count":42,"is_preprint":false},{"pmid":"36742296","id":"PMC_36742296","title":"Interleukin-18 and IL-18BP in inflammatory dermatological diseases.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36742296","citation_count":41,"is_preprint":false},{"pmid":"17951325","id":"PMC_17951325","title":"Free Interleukin (IL)-18 levels, and the impact of IL18 and IL18BP genetic variation, in CHD patients and healthy men.","date":"2007","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17951325","citation_count":32,"is_preprint":false},{"pmid":"22913567","id":"PMC_22913567","title":"Elevated levels of circulating IL-18BP and perturbed regulation of IL-18 in schizophrenia.","date":"2012","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/22913567","citation_count":29,"is_preprint":false},{"pmid":"33122671","id":"PMC_33122671","title":"IL-18 binding protein (IL-18BP) as a novel radiation countermeasure after radiation exposure in mice.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33122671","citation_count":28,"is_preprint":false},{"pmid":"39769266","id":"PMC_39769266","title":"IL-18 and IL-18BP: A Unique Dyad in Health and Disease.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39769266","citation_count":26,"is_preprint":false},{"pmid":"32659652","id":"PMC_32659652","title":"Interleukin 18 (IL-18) and its binding protein (IL-18BP) are increased in patients with epilepsy suggesting low-grade systemic 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Complete ORF isolation from cDNA libraries revealed a unique soluble antagonist sharing homology with viral proteins, distinct from IL-18Rα and IL-18Rβ chains. It forms a 1:1 high-affinity complex with IL-18 (Kd=400 pM) with a very low dissociation rate.\",\n      \"method\": \"IL-18 ligand affinity chromatography, protein microsequencing, cDNA library screening, in vitro binding/neutralization assays\",\n      \"journal\": \"Immune network\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — original biochemical purification, protein sequencing, and functional reconstitution; replicated across multiple subsequent studies confirming the Kd\",\n      \"pmids\": [\"38455460\", \"11497494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-18BP (isoform a) forms a 1:1 stoichiometric high-affinity complex with IL-18 (Kd=400 pM) with a very low dissociation rate, effectively blocking IL-18 bioactivity. A sandwich ELISA specific to IL-18BPa was developed and validated, showing no cross-reactivity with IL-18 or other IL-18BP isoforms (b, c, d). Using mass-action calculations, most circulating IL-18 in healthy individuals (~85%) is free, whereas in sepsis, the majority is bound to IL-18BPa.\",\n      \"method\": \"Sandwich ELISA, electrochemiluminescence assay, mass-action law calculations\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding characterization with quantitative affinity measurement replicated across multiple studies\",\n      \"pmids\": [\"11497494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IFN-γ induces IL-18BP expression in DLD-1 colon carcinoma cells via direct binding of STAT1 to a proximal gamma-activated sequence (GAS) element in the IL-18BP promoter. Mutational analysis showed this proximal GAS is pivotal; siRNA knockdown confirmed essential role of STAT1; EMSA and chromatin immunoprecipitation (ChIP) proved STAT1 binding to this specific GAS site. Maximal expression required de novo protein synthesis but was independent of IRF-1.\",\n      \"method\": \"Promoter mutational analysis, siRNA knockdown, EMSA, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods (mutagenesis, siRNA, EMSA, ChIP) in a single study establishing the STAT1/GAS transcriptional mechanism\",\n      \"pmids\": [\"19046253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Remifentanil upregulates hepatic IL-18BP expression at the transcriptional level via activation of STAT1 and C/EBPβ transcription factors. Actinomycin D abolished remifentanil-induced IL-18BP mRNA upregulation; luciferase reporter assay confirmed increased IL-18BP promoter transcription; Western blot and ChIP assays showed STAT1 and C/EBPβ activation and binding; silencing of either STAT1 or C/EBPβ blocked IL-18BP upregulation. The induced IL-18BP was functionally active, inhibiting IL-18-activated NF-κB phosphorylation.\",\n      \"method\": \"Actinomycin D inhibition, luciferase reporter assay, ChIP, Western blot, siRNA knockdown\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods (reporter assay, ChIP, siRNA, functional NF-κB readout) in single study\",\n      \"pmids\": [\"30089853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Epigenetic regulation by CpG methylation at a specific CpG site (CpG2) neighboring the γ-activated sequence (GAS) in the IL18BP promoter determines differential IFNγ-induced IL-18BP expression between monocytic and epithelial cells. CpG2 is constitutively methylated in monocytic but unmethylated in epithelial cells. 5-aza-2'-deoxycytidine (DNA demethylation) enhanced IFNγ-induced IL-18BP only in monocytic cells; demethylation impeded MeCP2 binding to CpG2, increased adjacent H3K9-acetylation, and enhanced RNA-polymerase-II recruitment to the IL18BP transcriptional start.\",\n      \"method\": \"5-aza-2'-deoxycytidine treatment, ChIP for MeCP2 and histone modifications, RNA-polymerase-II recruitment analysis, promoter CpG methylation analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal epigenetic methods (ChIP, demethylation treatment, histone modification analysis) in a single study\",\n      \"pmids\": [\"29409936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Inherited homozygous loss-of-function deletion in IL18BP causes IL-18BP deficiency in humans. In the absence of IL-18BP, excessive NK cell activation by IL-18 results in uncontrolled killing of human hepatocytes in vitro. Human IL-18 and IL-18BP are both secreted primarily by hepatocytes and macrophages in the liver. This establishes IL-18BP as an essential restraint on IL-18-driven NK cell cytotoxicity in the liver.\",\n      \"method\": \"Human genetic analysis (homozygous deletion), in vitro NK cell cytotoxicity assay with human hepatocytes, IL-18BP knockout functional studies\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic loss-of-function combined with direct in vitro functional rescue/cytotoxicity assay\",\n      \"pmids\": [\"31213488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-18BP is a high-affinity decoy receptor that is frequently upregulated in diverse human and mouse tumors and limits anti-tumor activity of IL-18 in vivo. Directed evolution was used to engineer 'decoy-resistant' IL-18 (DR-18) that maintains receptor signaling but is impervious to IL-18BP inhibition, demonstrating that the IL-18BP:IL-18 interaction is the mechanistic barrier to IL-18 anti-tumor efficacy.\",\n      \"method\": \"Directed evolution/protein engineering, mouse tumor models, flow cytometry for T cell phenotyping\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — engineering approach with in vivo functional validation across multiple tumor models, demonstrating IL-18BP as the mechanistic barrier\",\n      \"pmids\": [\"32581358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In human monocytic THP-1 cells stimulated with P. gingivalis LPS, both IL-18 and IL-18BPa are secreted. Addition of antibodies to IL-18BPa to stimulated cultures resulted in increased levels of free IL-18, directly demonstrating a specific neutralizing interaction between IL-18 and IL-18BPa in this cellular system. VIP (10⁻⁸M) inhibited both IL-18 and IL-18BPa secretion.\",\n      \"method\": \"ELISA, neutralizing antibody competition assay in THP-1 cell cultures\",\n      \"journal\": \"Journal of dental research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — antibody competition demonstrates functional IL-18:IL-18BPa interaction in cellular context, single lab with two methods\",\n      \"pmids\": [\"17720860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IL-18BPa:Fc significantly inhibited LPS/IL-12-induced IFN-γ and MMP-9 release from human whole blood cultures, demonstrating functional IL-18 blockade in a physiologically relevant ex vivo system. IL-18BPa:Fc cooperated additively with immunosuppressive drugs (dexamethasone, mycophenolic acid) to further reduce IFN-γ production.\",\n      \"method\": \"Human whole blood ex vivo culture, ELISA for IFN-γ and MMP-9\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean functional assay in primary human whole blood with defined readouts, single lab\",\n      \"pmids\": [\"12907250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A mouse monoclonal antibody (2A6H11) specific for rat IL-18BP was generated. Its binding epitope was mapped to amino acids 29-60 on IL-18BP. Critically, this antibody does not interfere with IL-18BP function (i.e., does not block IL-18 binding).\",\n      \"method\": \"Monoclonal antibody generation, epitope mapping, functional ELISA\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct epitope mapping and functional characterization of antibody binding site, single lab\",\n      \"pmids\": [\"12505199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LPS treatment of rats selectively upregulates IL-18BP mRNA in the liver (~12-fold above naive levels, peaking at 3h), whereas IL-18 mRNA expression in the liver was unaffected by LPS. This differential regulation suggests an endogenous feedback mechanism for controlling IL-18 activity during inflammatory responses.\",\n      \"method\": \"Real-time PCR of rat liver tissue after peripheral LPS injection\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single in vivo experiment with quantitative PCR, single lab\",\n      \"pmids\": [\"12788303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Bioinformatics analysis across 86 mammalian species shows IL-18BP is consistently most similar to IL-1R9 (IL-1R accessory protein-like 2). IL-1R9 and IL-1R8 share conserved amino acid sequences homologous to binding site A of human and viral IL-18BPs, conserved intron/exon boundaries, and protein structure, suggesting evolutionary relationship and potential IL-18 binding capacity.\",\n      \"method\": \"Bioinformatics/phylogenetic analysis of Ensembl and NCBI databases, protein structure comparison\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/bioinformatics only, no experimental validation of IL-1R9 binding IL-18\",\n      \"pmids\": [\"27881706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MD simulation analysis of all known IL-18–IL-18BP PDB crystal structures revealed that residues 68–81 of IL-18 adopt a disordered conformation in all IL-18–IL-18BP complexes but a 310-helical structure in IL-18–receptor complexes. C74 within this epitope can form an intermolecular disulfide bond in the human tetrameric IL-18–IL-18BP assembly. Simulations show the helical form of this epitope stabilizes the heterodimer by reducing backbone flexibility, and the exposed C74 sidechain in disordered form mediates self-assembly of IL-18–IL-18BP dimers.\",\n      \"method\": \"All-atom molecular dynamics simulations of PDB structures and computed models\",\n      \"journal\": \"Computational and structural biotechnology journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational only (MD simulations), no experimental validation of the proposed disulfide or helical state\",\n      \"pmids\": [\"37484491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In rainbow trout, recombinant IL-18BP (rIL-18BP) significantly downregulates NF-κB activity induced by IL-18 via its receptor complex (IL-18Rα + IL-18Rβ) in HEK293T cells, demonstrating conserved decoy receptor function. Co-IP assays showed IL-18Rβ forms a complex with MyD88, IRAK4, IRAK1, TRAF6, and TAB2, indicating IL-18Rβ is the signaling-competent subunit recruiting these downstream molecules.\",\n      \"method\": \"NF-κB reporter assay in HEK293T cells with chimeric receptor transfection, Co-immunoprecipitation\",\n      \"journal\": \"Developmental and comparative immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and functional reporter assay in a fish ortholog study, single lab\",\n      \"pmids\": [\"36496012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In Toxoplasma gondii infection, IFN-γ produced during infection induces high levels of IL-18BP, which restrains IL-18-mediated ILC and T cell responses. Antagonism of IL-18BP with a 'decoy-to-the-decoy' (D2D) construct (non-signaling IL-18 that sequesters IL-18BP) enhanced innate lymphoid cell and T cell responses and improved parasite control, establishing IL-18BP as a functional brake on IL-18 activity in vivo. DR-18 (IL-18 resistant to IL-18BP) promoted CD4+ T cell IFN-γ but also caused CD4+ T cell-mediated pathology.\",\n      \"method\": \"Mouse infection model with T. gondii, D2D and DR-18 protein treatment, flow cytometry for immune cell responses\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo functional epistasis with engineered IL-18BP antagonist and decoy-resistant IL-18, multiple readouts\",\n      \"pmids\": [\"36827187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"An anti-IL-18BP monoclonal antibody (COM503) was generated that blocks the IL-18BP:IL-18 interaction and displaces pre-complexed IL-18 from IL-18BP, thereby restoring free IL-18 activity and enhancing T and NK cell activation in vitro. In vivo, a surrogate anti-IL-18BP antibody caused pronounced tumor microenvironment-localized immune modulation (increased polyfunctional non-exhausted T and NK cells) without systemic inflammatory cytokine elevation, establishing IL-18BP blockade as a mechanism for TME-specific IL-18 release.\",\n      \"method\": \"Anti-IL-18BP antibody generation, in vitro displacement/neutralization assay, mouse tumor models, cytokine measurement in serum vs. TME\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional in vitro displacement assay combined with in vivo tumor model with mechanistic readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38592331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-92b-5p directly suppresses IL-18BP expression in microglia. Transfection of miR-92b-5p into activated microglia significantly decreased IL-18BP expression while increasing IL-18 mRNA; miR-92b-5p inhibitor reversed this effect. After spinal cord injury, miR-92b-5p is upregulated in the injured cord, correlating with decreased IL-18BP and increased IL-18 expression.\",\n      \"method\": \"miRNA transfection in primary microglia, qRT-PCR, intrathecal injection of miR-92b-5p inhibitor in mouse SCI model\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct miRNA manipulation with reciprocal expression changes, confirmed in vitro and in vivo, single lab\",\n      \"pmids\": [\"30915731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In an IL-18bp knockout mouse model, excess IL-18 activity (without IL-18BP restraint) caused NK cells to be inert/hypofunctional upon mousepox infection despite being hyperactivated at rest. IL-18bp KO mice succumbed to viremic MAS-like disease with poor virus-specific CTL expansion, establishing that IL-18BP is required to maintain NK cell responsiveness to infectious challenge by preventing IL-18-driven NK hypoactivation.\",\n      \"method\": \"Il18bp knockout mouse model, mousepox infection challenge, NK cell transfer rescue experiments, flow cytometry, viral clearance assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO with defined phenotypic readout and NK rescue experiment, but preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.07.04.663237\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"IL-18BP is a secreted high-affinity soluble decoy receptor (Kd ~400 pM, very slow off-rate) that neutralizes IL-18 by forming a 1:1 non-signaling complex, thereby blocking IL-18 from engaging its signaling receptors IL-18Rα/IL-18Rβ; its expression is transcriptionally induced by IFN-γ via direct STAT1 binding to a proximal GAS element in its promoter—a process epigenetically gated by CpG methylation in monocytes but not epithelial cells—creating a negative feedback loop, and its constitutive and induced secretion by hepatocytes and macrophages is essential in vivo for restraining IL-18-driven NK cell cytotoxicity against hepatocytes and for preventing pathological hyperinflammation in multiple disease contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL-18BP is a secreted high-affinity decoy receptor that neutralizes the pro-inflammatory cytokine IL-18, serving as a key brake on IL-18-driven immune activation [#0, #5]. Originally purified from human urine as a 40-residue soluble antagonist distinct from the IL-18R\\u03b1/\\u03b2 signaling chains, it forms a 1:1 stoichiometric complex with IL-18 (Kd ~400 pM) with a very slow dissociation rate, sequestering the cytokine and blocking its engagement of the signaling receptor and downstream NF-\\u03baB activation [#0, #1, #3]. By mass-action, this binding determines the free IL-18 pool: most circulating IL-18 is free in health but largely bound in sepsis [#1]. IL-18BP expression is transcriptionally induced by IFN-\\u03b3 through direct STAT1 binding to a proximal GAS element in its promoter, constituting a negative feedback loop, and is co-regulated by C/EBP\\u03b2 in hepatocytes; this induction is epigenetically gated by CpG methylation adjacent to the GAS element, which restricts IFN-\\u03b3 responsiveness in monocytes relative to epithelial cells [#2, #3, #4]. In vivo, IL-18BP secreted by hepatocytes and macrophages restrains IL-18-driven NK cell cytotoxicity against hepatocytes, and inherited homozygous loss-of-function deletion causes human IL-18BP deficiency with uncontrolled NK-mediated hepatocyte killing [#5]. The same neutralizing axis acts as a barrier to IL-18 anti-tumor activity and an immune brake during infection: tumors upregulate IL-18BP to limit IL-18 efficacy, and engineered decoy-resistant IL-18 or anti-IL-18BP antibodies that displace pre-bound IL-18 restore T and NK cell activation [#6, #14, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the existence of a soluble, secreted IL-18 antagonist distinct from the membrane IL-18 receptor chains, defining a new mode of IL-18 regulation.\",\n      \"evidence\": \"IL-18 ligand affinity chromatography from human urine, protein microsequencing, cDNA cloning, and in vitro binding/neutralization\",\n      \"pmids\": [\"38455460\", \"11497494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve in vivo physiological role\", \"Homology to viral proteins noted but structural basis of binding undefined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Quantified the IL-18BPa:IL-18 interaction and showed that decoy occupancy controls the free IL-18 pool, distinguishing health from sepsis.\",\n      \"evidence\": \"Isoform-specific sandwich ELISA, electrochemiluminescence, and mass-action calculations of free vs. bound IL-18\",\n      \"pmids\": [\"11497494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of other isoforms (b, c, d) not established\", \"Did not address tissue source of circulating IL-18BP\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the transcriptional mechanism of IL-18BP induction, showing IFN-\\u03b3 drives expression via direct STAT1 binding to a proximal GAS element, formalizing a negative feedback loop.\",\n      \"evidence\": \"Promoter mutagenesis, siRNA knockdown, EMSA, and ChIP in DLD-1 colon carcinoma cells\",\n      \"pmids\": [\"19046253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"IRF-1 independence noted but identity of the required de novo synthesized protein unknown\", \"Cell-type generality of GAS dependence not addressed in this study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed expression is epigenetically gated and co-regulated by additional factors, explaining cell-type-specific IFN-\\u03b3 responsiveness.\",\n      \"evidence\": \"CpG methylation/demethylation (5-aza), MeCP2 and histone ChIP, RNA-Pol II recruitment (monocytic vs. epithelial); plus STAT1/C/EBP\\u03b2 reporter, ChIP, and siRNA in hepatic cells\",\n      \"pmids\": [\"29409936\", \"30089853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism setting differential CpG2 methylation between lineages unknown\", \"Interplay of C/EBP\\u03b2 and STAT1 at the promoter not structurally resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established IL-18BP as a physiologically essential restraint on IL-18, with human loss-of-function causing uncontrolled NK-mediated hepatocyte killing.\",\n      \"evidence\": \"Human homozygous deletion genetics and in vitro NK cytotoxicity assays against human hepatocytes\",\n      \"pmids\": [\"31213488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish full spectrum of human disease phenotype\", \"Relative contribution of hepatocyte vs. macrophage IL-18BP sources not partitioned\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that the IL-18BP:IL-18 interaction is the mechanistic barrier limiting IL-18 anti-tumor activity, enabling therapeutic decoy-resistant IL-18.\",\n      \"evidence\": \"Directed evolution of decoy-resistant IL-18 (DR-18) and mouse tumor models with T cell phenotyping\",\n      \"pmids\": [\"32581358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Drivers of tumor IL-18BP upregulation not fully defined\", \"Did not address normal-tissue toxicity of bypassing the decoy\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Confirmed IL-18BP as an in vivo functional brake on infection-driven lymphoid responses, with engineered antagonists revealing the protective-versus-pathological balance of unleashing IL-18.\",\n      \"evidence\": \"Mouse T. gondii infection with D2D (decoy-to-the-decoy) and DR-18 treatment, flow cytometry, parasite control readouts\",\n      \"pmids\": [\"36827187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Threshold separating beneficial IL-18 release from CD4 T-cell pathology undefined\", \"Generalizability across pathogens not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Validated pharmacological IL-18BP blockade by antibody that displaces pre-bound IL-18, achieving tumor-localized immune activation without systemic inflammation.\",\n      \"evidence\": \"Anti-IL-18BP antibody (COM503) in vitro displacement/neutralization and mouse tumor models comparing serum vs. TME cytokines\",\n      \"pmids\": [\"38592331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis of TME-restricted versus systemic effect not mechanistically resolved\", \"Durability and resistance to blockade not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed that loss of IL-18BP restraint paradoxically renders NK cells hypofunctional during infection, framing IL-18BP as required to preserve NK responsiveness.\",\n      \"evidence\": \"Il18bp knockout mouse, mousepox challenge, NK transfer rescue, viral clearance assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.07.04.663237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Molecular basis of IL-18-driven NK exhaustion/hypoactivation undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IL-18BP structurally engages IL-18 to occlude receptor binding, and how higher-order self-assembly contributes to neutralization in vivo, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Proposed C74 disulfide-mediated tetramer assembly is computational only and unvalidated experimentally\", \"No experimental structure of the human IL-18BP self-assembled state confirmed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 6, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 5, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 6, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IL18\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"IL18BP","tier":"IDENTITY","verdict":"Identity concern","subtype":"corpus_ungrounded","uniprot_band":"sparse","rules_fired":"R1","issue":"R1: gene named in 9/52 (17%) of its own corpus abstracts (< 25%) — corpus likely a paralog/alias collision"},"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}