{"gene":"IL18BP","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1999,"finding":"IL-18BP was originally discovered by subjecting concentrated human urine to an IL-18 ligand affinity column, revealing a novel soluble antagonist of IL-18 that shares homology with viral proteins and is distinct from the IL-18Rα and IL-18Rβ chains. Recombinant IL-18BP potently neutralizes IL-18 activity in vitro and in vivo.","method":"IL-18 ligand affinity chromatography, protein microsequencing, cDNA library screening, recombinant protein production, in vitro neutralization assays","journal":"Immune network","confidence":"High","confidence_rationale":"Tier 1 — original discovery via biochemical purification and functional characterization, foundational paper","pmids":["38455460"],"is_preprint":false},{"year":2001,"finding":"IL-18BP forms a 1:1 high-affinity complex with IL-18 (Kd=400 pM) with a very low dissociation rate, effectively blocking IL-18 biological activity. Circulating IL-18BPa in healthy humans is ~2.15 ng/ml; in sepsis it rises to ~21.9 ng/ml, binding most circulating IL-18 and substantially reducing free IL-18.","method":"Sandwich ELISA for IL-18BPa, electrochemiluminescence assay for IL-18, mass action law calculation of free IL-18, serum measurements in healthy individuals and sepsis patients","journal":"Cytokine","confidence":"High","confidence_rationale":"Tier 1–2 — quantitative binding characterization and in vivo measurement, widely replicated","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, establishing a negative feedback mechanism. IRF-1 is not required, and maximal expression requires de novo protein synthesis.","method":"Mutational analysis of IL-18BP promoter, siRNA knockdown of STAT1, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), actinomycin D treatment","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods (EMSA, ChIP, mutagenesis, siRNA) in single study","pmids":["19046253"],"is_preprint":false},{"year":2018,"finding":"Remifentanil upregulates hepatic IL-18BP expression through transcriptional activation of the IL-18BP promoter, requiring STAT1 and C/EBPβ as key transcription factors. The upregulated IL-18BP inhibits IL-18-activated NF-κB p65 phosphorylation in hepatocytes.","method":"qRT-PCR, Western blot, luciferase reporter assay, ChIP, siRNA knockdown of STAT1 and C/EBPβ, actinomycin D treatment, IL-18BP siRNA knockdown functional rescue","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 1 — reconstitution-level evidence with reporter assay, ChIP, and functional siRNA rescue","pmids":["30089853"],"is_preprint":false},{"year":2018,"finding":"CpG methylation at a single CpG site (CpG2) neighboring the GAS element in the IL-18BP promoter epigenetically silences IFN-γ-induced IL-18BP expression in monocytic cells but not epithelial cells. Demethylation by 5-aza-2'-deoxycytidine impedes MeCP2 interaction with CpG2, increases adjacent histone H3K9-acetylation, and enhances RNA polymerase II recruitment to the IL-18BP transcriptional start site.","method":"5-aza-2'-deoxycytidine treatment, bisulfite sequencing, promoter analysis, MeCP2 binding assay, histone H3K9 acetylation assay, RNA polymerase II ChIP","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"High","confidence_rationale":"Tier 1–2 — multiple chromatin-level mechanistic methods with functional consequence","pmids":["29409936"],"is_preprint":false},{"year":2019,"finding":"Inherited human IL-18BP deficiency (homozygous 40-nucleotide deletion, loss-of-function) underlies fulminant hepatitis A virus hepatitis. Human IL-18 and IL-18BP are both secreted predominantly by hepatocytes and macrophages in the liver. In the absence of IL-18BP, excessive NK cell activation by IL-18 results in uncontrolled killing of human hepatocytes in vitro.","method":"Whole-exome sequencing, loss-of-function validation of the IL-18BP variant, in vitro NK cell killing assay of human hepatocytes, immunohistochemistry of liver","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — human genetic loss-of-function with in vitro functional validation, clear mechanistic link","pmids":["31213488"],"is_preprint":false},{"year":2020,"finding":"IL-18BP is frequently upregulated in diverse human and mouse tumours (acting as a secreted immune checkpoint), limits the anti-tumour activity of IL-18, and can be overcome by engineering 'decoy-resistant' IL-18 (DR-18) that maintains IL-18 receptor signalling but is impervious to IL-18BP inhibition. DR-18 promotes poly-functional effector CD8+ T cells, reduces TOX-expressing exhausted CD8+ T cells, expands TCF1+ precursor CD8+ T cells, and enhances NK cell maturation.","method":"Directed evolution of IL-18, mouse tumour models, CD8+ T cell and NK cell phenotyping by flow cytometry, in vivo anti-tumour efficacy experiments, transcriptional profiling","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — directed evolution approach with multiple orthogonal in vivo readouts, highly cited","pmids":["32581358"],"is_preprint":false},{"year":2003,"finding":"IL-18BPa:Fc fusion protein significantly inhibits LPS/IL-12-induced IFN-γ and MMP-9 release from human whole blood cultures and cooperates additively with immunosuppressive drugs (dexamethasone, mycophenolic acid) to further reduce IFN-γ production.","method":"Human whole blood culture assay, ELISA for IFN-γ and MMP-9, pharmacological combination experiments with immunosuppressive drugs","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — clean functional assay in human whole blood but single lab","pmids":["12907250"],"is_preprint":false},{"year":2007,"finding":"Porphyromonas gingivalis LPS induces both IL-18 and IL-18BPa secretion in human THP-1 monocytes. Addition of antibodies to IL-18BPa to stimulated cultures results in increased free IL-18, confirming specific IL-18/IL-18BPa interaction in this system. VIP (10⁻⁸M) inhibits both IL-18 and IL-18BP secretion.","method":"ELISA, neutralizing antibody blockade of IL-18BPa in THP-1 cell culture, VIP inhibition assay","journal":"Journal of dental research","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, antibody blockade confirms IL-18/IL-18BP interaction but limited mechanistic depth","pmids":["17720860"],"is_preprint":false},{"year":2003,"finding":"LPS selectively upregulates IL-18BP mRNA (~12-fold) but not IL-18 mRNA in rat liver within 3 hours, suggesting IL-18BP induction is a regulatory mechanism to control IL-18 activity during systemic inflammation.","method":"Real-time PCR measurement of IL-18BP and IL-18 mRNA in rat liver following peripheral LPS injection","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 3 — single in vivo experiment with clear differential regulation, single lab","pmids":["12788303"],"is_preprint":false},{"year":2016,"finding":"Bioinformatic and phylogenetic analysis reveals that IL-18BP is evolutionarily most similar to IL-1R9 (IL-1R accessory protein-like 2) across mammalian species, sharing conserved intron/exon boundaries, protein structure, and key binding site amino acids, suggesting IL-18BP and IL-1R9 share a common evolutionary origin and that IL-1R9 and IL-1R8 may bind IL-18.","method":"Bioinformatics database analysis (Ensembl, NCBI), phylogenetic analysis, protein structure comparison, binding site amino acid alignment across 86 species","journal":"Journal of immunology","confidence":"Low","confidence_rationale":"Tier 4 — computational/bioinformatics only, no experimental validation of IL-1R9/IL-18 interaction","pmids":["27881706"],"is_preprint":false},{"year":2023,"finding":"MD simulations of all known IL-18–IL-18BP crystal complexes show that a short epitope of IL-18 (amino acids 68–81), which is disordered in IL-18–IL-18BP complexes but adopts a 3₁₀ helix in receptor complexes, stabilizes the IL-18BP heterodimer. C74 within this epitope can form an intermolecular disulfide bond in the self-assembled human IL-18–IL-18BP tetramer, contributing to complex stability.","method":"All-atom molecular dynamics simulations of PDB structures and computed complex models, analysis of intermolecular disulfide bond formation","journal":"Computational and structural biotechnology journal","confidence":"Low","confidence_rationale":"Tier 4 — computational modeling only, no experimental structural validation","pmids":["37484491"],"is_preprint":false},{"year":2023,"finding":"IL-18BP functions as a decoy receptor that limits endogenous IL-18 activity during Toxoplasma gondii infection; antagonism of IL-18BP with a 'decoy-to-the-decoy' (D2D) IL-18 construct (which binds IL-18BP but does not signal) releases IL-18 and enhances innate lymphoid cell and T cell responses and parasite control, whereas IL-18BP-resistant DR-18 enhances CD4+ T cell IFN-γ but causes pathology.","method":"Mouse infection model, D2D IL-18 construct, DR-18 construct, flow cytometry, IFN-γ measurement, parasite burden quantification","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — engineered protein tools and in vivo genetic/pharmacological approaches with multiple readouts","pmids":["36827187"],"is_preprint":false},{"year":2019,"finding":"miR-92b-5p directly suppresses IL-18BP expression in microglia; transfection with miR-92b-5p decreases IL-18BP and increases IL-18 mRNA, while miR-92b-5p inhibitor reverses this. In a mouse spinal cord injury model, miR-92b-5p inhibitor intrathecal injection increases IL-18BP and reduces inflammatory mediators (iNOS, TNF-α, IL-1β), improving locomotor function.","method":"miRNA transfection and inhibitor treatment in microglia, qRT-PCR, Western blot, in vivo spinal cord injury model, intrathecal injection, Basso Mouse Scale locomotor evaluation","journal":"European review for medical and pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 — in vitro and in vivo data connecting miR-92b-5p to IL-18BP regulation, single lab","pmids":["30915731"],"is_preprint":false},{"year":2024,"finding":"IL-18BP alleviates HSR-induced anxiety-like behavior in mice by inhibiting the IL-18R-NLRP3 signaling pathway in astrocytes, reducing astrocytic activation, cleaved caspase-1, GSDMD, and pyroptosis-associated factors; these effects are partially reversed by the NLRP3 agonist nigericin and are absent in astrocyte-specific NLRP3 knockout mice.","method":"Mouse hemorrhagic shock/resuscitation model, IL-18BP intraperitoneal injection, open-field and elevated plus maze behavioral tests, Western blot (caspase-1, GSDMD), immunofluorescence, astrocyte-specific NLRP3 KO mice, NLRP3 agonist nigericin rescue experiment","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic rescue (NLRP3 KO) and pharmacological (nigericin) confirmation in vivo, single lab","pmids":["36269543"],"is_preprint":false},{"year":2024,"finding":"Anti-IL-18BP monoclonal antibody (COM503) blocks the IL-18BP:IL-18 interaction and displaces pre-complexed IL-18, restoring free IL-18 activity and enhancing T- and NK-cell activation in vitro. In vivo, surrogate anti-IL-18BP induces tumor-localized immune modulation (increased polyfunctional non-exhausted T and NK cells) without systemic inflammatory cytokine elevation, demonstrating that IL-18BP sequestration in the TME is the primary mechanism suppressing IL-18.","method":"Anti-IL-18BP antibody generation, displacement assay for pre-complexed IL-18, T/NK cell activation in vitro assays, multiple syngeneic mouse tumor models, TME immune phenotyping by flow cytometry, serum cytokine measurement","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro displacement assay plus multiple in vivo tumor models with mechanistic TME analysis","pmids":["38592331"],"is_preprint":false},{"year":2022,"finding":"In rainbow trout, recombinant IL-18BP functions as a decoy receptor that downregulates IL-18-induced NF-κB activation in HEK293T cells, demonstrating conserved inhibitory function. Co-IP assays showed IL-18Rβ forms a complex with MyD88, IRAK4, IRAK1, TRAF6, and TAB2, placing IL-18BP inhibition upstream of this signaling complex.","method":"Transfection of chimeric receptors in HEK293T cells, NF-κB reporter assay, co-immunoprecipitation","journal":"Developmental and comparative immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 — functional assay plus Co-IP in a non-mammalian ortholog system, confirms conserved mechanism","pmids":["36496012"],"is_preprint":false},{"year":2023,"finding":"IL-18BP (as APB-R3, an albumin-binding long-acting recombinant form) directly inactivates IL-18 and alleviates liver inflammation and splenomegaly in IL-18BP knockout mice with macrophage activation syndrome, and controls skin inflammation in atopic dermatitis, demonstrating that IL-18BP blockade of IL-18 is sufficient to suppress these inflammatory phenotypes.","method":"IL-18BP knockout mouse MAS model, APB-R3 treatment, liver and spleen pathology assessment, atopic dermatitis mouse model, pharmacokinetics measurement","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 — IL-18BP KO mouse model plus pharmacological rescue provides direct mechanistic evidence","pmids":["37918054"],"is_preprint":false},{"year":2025,"finding":"In Il18bp KO mice, NK cells become inert upon mousepox infection and fail to activate or expand, resulting in viremic MAS and poor viral clearance, demonstrating that IL-18BP is required for proper NK cell function during viral infection and that its absence leads to NK cell hypoactivation alongside CTL hyperactivation.","method":"Il18bp knockout mice, mousepox infection model, NK cell transfer rescue experiment, CTL expansion and viral clearance assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with in vivo rescue by NK cell transfer; 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 decoy receptor (Kd ~400 pM, 1:1 stoichiometry) that binds mature IL-18 with a very slow off-rate to block its interaction with IL-18Rα/IL-18Rβ and downstream MyD88-IRAK-TRAF6-NF-κB/IFN-γ signaling; its expression is constitutive in liver and induced strongly by IFN-γ through direct STAT1 binding to a proximal GAS element in its promoter (with cell-type-specific epigenetic gating by CpG methylation in monocytes), creating a negative feedback loop; in vivo, IL-18BP deficiency unleashes NK cell-mediated hepatocyte killing and dysregulates the IL-18/NK/CTL axis during viral infection, while tumour-upregulated IL-18BP acts as an immune checkpoint that can be overcome by IL-18BP-resistant IL-18 variants or anti-IL-18BP antibodies."},"narrative":{"teleology":[{"year":1999,"claim":"The existence of a soluble, non-receptor antagonist of IL-18 was unknown; affinity purification from human urine identified IL-18BP as a novel secreted protein homologous to viral IL-18-binding proteins that potently neutralizes IL-18 in vitro and in vivo, establishing a new class of cytokine regulation.","evidence":"IL-18 ligand affinity chromatography of concentrated human urine, protein microsequencing, cDNA cloning, recombinant protein neutralization assays","pmids":["38455460"],"confidence":"High","gaps":["Binding affinity and stoichiometry not yet quantified","Endogenous expression sites and regulation unknown","Mechanism of action at the receptor level unresolved"]},{"year":2001,"claim":"Quantitative binding parameters were established: IL-18BP forms a 1:1 complex with IL-18 at Kd ~400 pM with a very slow off-rate, and circulating levels rise ~10-fold in sepsis to sequester most free IL-18, resolving how the decoy functions stoichiometrically in vivo.","evidence":"Sandwich ELISA and electrochemiluminescence assay for IL-18BPa and IL-18 in healthy and sepsis sera, mass action law calculations","pmids":["11497494"],"confidence":"High","gaps":["Structural basis for high-affinity binding not determined","Source tissues responsible for elevated circulating IL-18BP during inflammation unknown"]},{"year":2003,"claim":"The question of how IL-18BP is regulated during inflammation was addressed: LPS selectively induces IL-18BP but not IL-18 mRNA in liver, while IL-18BPa:Fc blocks LPS/IL-12-induced IFN-γ and MMP-9 from human blood, confirming IL-18BP as an endogenous brake on IL-18-mediated inflammation.","evidence":"Real-time PCR in rat liver after LPS, human whole blood culture with IL-18BPa:Fc and ELISA readout","pmids":["12788303","12907250"],"confidence":"Medium","gaps":["Transcription factor(s) driving LPS-induced IL-18BP expression unidentified","In vivo pharmacokinetics of IL-18BPa:Fc not established"]},{"year":2008,"claim":"The transcriptional mechanism of IFN-γ-induced IL-18BP expression was dissected, showing that STAT1 binds directly to a proximal GAS element in the IL-18BP promoter independently of IRF-1, establishing the molecular basis for the IFN-γ–IL-18BP negative feedback loop.","evidence":"EMSA, ChIP for STAT1, promoter mutagenesis, siRNA knockdown in DLD-1 cells","pmids":["19046253"],"confidence":"High","gaps":["Additional transcription factor cooperativity not fully explored","Whether this GAS-dependent mechanism operates identically across all cell types unclear"]},{"year":2018,"claim":"Cell-type-specific epigenetic gating of IL-18BP induction was revealed: CpG methylation at a single site adjacent to the GAS element recruits MeCP2 and represses H3K9 acetylation and RNA Pol II loading in monocytes but not epithelial cells, explaining why monocytes are refractory to IFN-γ-driven IL-18BP expression. Separately, hepatic IL-18BP transcription was shown to require both STAT1 and C/EBPβ.","evidence":"Bisulfite sequencing, 5-aza-dC treatment, MeCP2 binding assay, H3K9ac and Pol II ChIP in monocytic vs. epithelial cells; luciferase reporter, ChIP, and siRNA rescue in hepatocytes","pmids":["29409936","30089853"],"confidence":"High","gaps":["Whether CpG methylation is dynamically altered during monocyte differentiation or activation untested","Full set of tissue-specific cofactors not catalogued"]},{"year":2019,"claim":"The first human disease caused by IL-18BP deficiency was identified: a homozygous 40-nt deletion abolishing IL-18BP function led to fulminant hepatitis A, with unchecked IL-18-driven NK cell killing of hepatocytes, establishing IL-18BP as essential for hepatic immune homeostasis.","evidence":"Whole-exome sequencing of affected individual, loss-of-function validation, in vitro NK cell cytotoxicity assay against human hepatocytes, liver immunohistochemistry","pmids":["31213488"],"confidence":"High","gaps":["Whether other viral hepatitides are similarly gated by IL-18BP deficiency unknown","Contribution of other IL-18BP isoforms not assessed"]},{"year":2020,"claim":"IL-18BP was recognized as a tumor-associated immune checkpoint: tumors upregulate IL-18BP to neutralize IL-18 in the microenvironment, and a directed-evolution-derived decoy-resistant IL-18 (DR-18) bypasses IL-18BP, rescuing polyfunctional CD8+ T cells, reducing T cell exhaustion, and promoting NK cell maturation for anti-tumor immunity.","evidence":"Directed evolution of IL-18, multiple syngeneic mouse tumor models, flow cytometric T and NK cell phenotyping, transcriptional profiling","pmids":["32581358"],"confidence":"High","gaps":["Mechanism by which tumors upregulate IL-18BP not defined","Whether DR-18 causes systemic inflammatory toxicity in long-term models unclear"]},{"year":2023,"claim":"The in vivo role of IL-18BP during infection was further refined: a 'decoy-to-the-decoy' IL-18 construct that sequesters IL-18BP without signaling enhances innate lymphoid cell and T cell responses during Toxoplasma gondii infection, while IL-18BP knockout mice develop macrophage activation syndrome-like liver inflammation that is rescued by recombinant IL-18BP.","evidence":"D2D and DR-18 constructs in mouse infection models with flow cytometry and parasite burden; IL-18BP KO mouse MAS model with APB-R3 pharmacological rescue","pmids":["36827187","37918054"],"confidence":"High","gaps":["Whether the D2D approach is applicable to other IL-18BP-dominant disease settings untested","Long-term consequences of IL-18BP blockade on immune tolerance unknown"]},{"year":2024,"claim":"Therapeutic targeting of IL-18BP in tumors was validated: an anti-IL-18BP monoclonal antibody (COM503) displaces pre-complexed IL-18 and restores tumor-localized T and NK cell activation without systemic cytokine elevation, demonstrating that IL-18BP sequestration in the TME is the dominant mechanism suppressing anti-tumor IL-18 activity.","evidence":"Antibody displacement assay, T/NK cell activation in vitro, multiple syngeneic mouse tumor models, TME immune phenotyping, serum cytokine measurement","pmids":["38592331"],"confidence":"High","gaps":["Efficacy in human tumors not yet demonstrated","Structural basis of antibody-mediated IL-18 displacement from IL-18BP unresolved"]},{"year":null,"claim":"Key unresolved questions include the structural basis of the IL-18BP–IL-18 interaction at atomic resolution validated experimentally, the full catalogue of tissue- and disease-specific transcriptional and post-transcriptional regulators of IL-18BP, and whether IL-18BP has IL-18-independent functions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No experimentally validated high-resolution structure of the human IL-18BP–IL-18 complex","Post-translational modifications and secretion mechanism of IL-18BP uncharacterized","Potential IL-18-independent roles of IL-18BP not investigated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,6,12,15]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0,1,6,15]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,5,6,15]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,5,6,12,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,6,16]}],"complexes":[],"partners":["IL18","STAT1","CEBPB","MECP2"],"other_free_text":[]},"mechanistic_narrative":"IL-18BP is a secreted high-affinity decoy receptor that neutralizes IL-18 by forming a 1:1 complex (Kd ~400 pM) with an extremely slow dissociation rate, thereby preventing IL-18 from engaging IL-18Rα/IL-18Rβ and blocking downstream MyD88–IRAK–TRAF6–NF-κB signaling and IFN-γ production [PMID:11497494, PMID:36496012]. Its transcription is induced by IFN-γ via direct STAT1 binding to a proximal GAS element in the IL-18BP promoter, creating a negative feedback loop, with cell-type-specific modulation by CpG methylation at a single site adjacent to the GAS element that silences expression in monocytes but not epithelial cells [PMID:19046253, PMID:29409936]. Homozygous loss-of-function mutations in IL18BP cause fulminant viral hepatitis through unrestrained IL-18-driven NK cell killing of hepatocytes [PMID:31213488]. In the tumor microenvironment, IL-18BP is upregulated as a secreted immune checkpoint that suppresses anti-tumor T and NK cell responses, an activity that can be overcome by decoy-resistant IL-18 variants or anti-IL-18BP antibodies that displace pre-complexed IL-18 [PMID:32581358, PMID:38592331]."},"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":289,"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":232,"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":91,"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":46,"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":38,"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 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Recombinant IL-18BP potently neutralizes IL-18 activity in vitro and in vivo.\",\n      \"method\": \"IL-18 ligand affinity chromatography, protein microsequencing, cDNA library screening, recombinant protein production, in vitro neutralization assays\",\n      \"journal\": \"Immune network\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original discovery via biochemical purification and functional characterization, foundational paper\",\n      \"pmids\": [\"38455460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-18BP forms a 1:1 high-affinity complex with IL-18 (Kd=400 pM) with a very low dissociation rate, effectively blocking IL-18 biological activity. Circulating IL-18BPa in healthy humans is ~2.15 ng/ml; in sepsis it rises to ~21.9 ng/ml, binding most circulating IL-18 and substantially reducing free IL-18.\",\n      \"method\": \"Sandwich ELISA for IL-18BPa, electrochemiluminescence assay for IL-18, mass action law calculation of free IL-18, serum measurements in healthy individuals and sepsis patients\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — quantitative binding characterization and in vivo measurement, widely replicated\",\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, establishing a negative feedback mechanism. IRF-1 is not required, and maximal expression requires de novo protein synthesis.\",\n      \"method\": \"Mutational analysis of IL-18BP promoter, siRNA knockdown of STAT1, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), actinomycin D treatment\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods (EMSA, ChIP, mutagenesis, siRNA) in single study\",\n      \"pmids\": [\"19046253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Remifentanil upregulates hepatic IL-18BP expression through transcriptional activation of the IL-18BP promoter, requiring STAT1 and C/EBPβ as key transcription factors. The upregulated IL-18BP inhibits IL-18-activated NF-κB p65 phosphorylation in hepatocytes.\",\n      \"method\": \"qRT-PCR, Western blot, luciferase reporter assay, ChIP, siRNA knockdown of STAT1 and C/EBPβ, actinomycin D treatment, IL-18BP siRNA knockdown functional rescue\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution-level evidence with reporter assay, ChIP, and functional siRNA rescue\",\n      \"pmids\": [\"30089853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CpG methylation at a single CpG site (CpG2) neighboring the GAS element in the IL-18BP promoter epigenetically silences IFN-γ-induced IL-18BP expression in monocytic cells but not epithelial cells. Demethylation by 5-aza-2'-deoxycytidine impedes MeCP2 interaction with CpG2, increases adjacent histone H3K9-acetylation, and enhances RNA polymerase II recruitment to the IL-18BP transcriptional start site.\",\n      \"method\": \"5-aza-2'-deoxycytidine treatment, bisulfite sequencing, promoter analysis, MeCP2 binding assay, histone H3K9 acetylation assay, RNA polymerase II ChIP\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple chromatin-level mechanistic methods with functional consequence\",\n      \"pmids\": [\"29409936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Inherited human IL-18BP deficiency (homozygous 40-nucleotide deletion, loss-of-function) underlies fulminant hepatitis A virus hepatitis. Human IL-18 and IL-18BP are both secreted predominantly by hepatocytes and macrophages in the liver. In the absence of IL-18BP, excessive NK cell activation by IL-18 results in uncontrolled killing of human hepatocytes in vitro.\",\n      \"method\": \"Whole-exome sequencing, loss-of-function validation of the IL-18BP variant, in vitro NK cell killing assay of human hepatocytes, immunohistochemistry of liver\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human genetic loss-of-function with in vitro functional validation, clear mechanistic link\",\n      \"pmids\": [\"31213488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-18BP is frequently upregulated in diverse human and mouse tumours (acting as a secreted immune checkpoint), limits the anti-tumour activity of IL-18, and can be overcome by engineering 'decoy-resistant' IL-18 (DR-18) that maintains IL-18 receptor signalling but is impervious to IL-18BP inhibition. DR-18 promotes poly-functional effector CD8+ T cells, reduces TOX-expressing exhausted CD8+ T cells, expands TCF1+ precursor CD8+ T cells, and enhances NK cell maturation.\",\n      \"method\": \"Directed evolution of IL-18, mouse tumour models, CD8+ T cell and NK cell phenotyping by flow cytometry, in vivo anti-tumour efficacy experiments, transcriptional profiling\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — directed evolution approach with multiple orthogonal in vivo readouts, highly cited\",\n      \"pmids\": [\"32581358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IL-18BPa:Fc fusion protein significantly inhibits LPS/IL-12-induced IFN-γ and MMP-9 release from human whole blood cultures and cooperates additively with immunosuppressive drugs (dexamethasone, mycophenolic acid) to further reduce IFN-γ production.\",\n      \"method\": \"Human whole blood culture assay, ELISA for IFN-γ and MMP-9, pharmacological combination experiments with immunosuppressive drugs\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean functional assay in human whole blood but single lab\",\n      \"pmids\": [\"12907250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Porphyromonas gingivalis LPS induces both IL-18 and IL-18BPa secretion in human THP-1 monocytes. Addition of antibodies to IL-18BPa to stimulated cultures results in increased free IL-18, confirming specific IL-18/IL-18BPa interaction in this system. VIP (10⁻⁸M) inhibits both IL-18 and IL-18BP secretion.\",\n      \"method\": \"ELISA, neutralizing antibody blockade of IL-18BPa in THP-1 cell culture, VIP inhibition assay\",\n      \"journal\": \"Journal of dental research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, antibody blockade confirms IL-18/IL-18BP interaction but limited mechanistic depth\",\n      \"pmids\": [\"17720860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LPS selectively upregulates IL-18BP mRNA (~12-fold) but not IL-18 mRNA in rat liver within 3 hours, suggesting IL-18BP induction is a regulatory mechanism to control IL-18 activity during systemic inflammation.\",\n      \"method\": \"Real-time PCR measurement of IL-18BP and IL-18 mRNA in rat liver following peripheral LPS injection\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single in vivo experiment with clear differential regulation, single lab\",\n      \"pmids\": [\"12788303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Bioinformatic and phylogenetic analysis reveals that IL-18BP is evolutionarily most similar to IL-1R9 (IL-1R accessory protein-like 2) across mammalian species, sharing conserved intron/exon boundaries, protein structure, and key binding site amino acids, suggesting IL-18BP and IL-1R9 share a common evolutionary origin and that IL-1R9 and IL-1R8 may bind IL-18.\",\n      \"method\": \"Bioinformatics database analysis (Ensembl, NCBI), phylogenetic analysis, protein structure comparison, binding site amino acid alignment across 86 species\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational/bioinformatics only, no experimental validation of IL-1R9/IL-18 interaction\",\n      \"pmids\": [\"27881706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MD simulations of all known IL-18–IL-18BP crystal complexes show that a short epitope of IL-18 (amino acids 68–81), which is disordered in IL-18–IL-18BP complexes but adopts a 3₁₀ helix in receptor complexes, stabilizes the IL-18BP heterodimer. C74 within this epitope can form an intermolecular disulfide bond in the self-assembled human IL-18–IL-18BP tetramer, contributing to complex stability.\",\n      \"method\": \"All-atom molecular dynamics simulations of PDB structures and computed complex models, analysis of intermolecular disulfide bond formation\",\n      \"journal\": \"Computational and structural biotechnology journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational modeling only, no experimental structural validation\",\n      \"pmids\": [\"37484491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-18BP functions as a decoy receptor that limits endogenous IL-18 activity during Toxoplasma gondii infection; antagonism of IL-18BP with a 'decoy-to-the-decoy' (D2D) IL-18 construct (which binds IL-18BP but does not signal) releases IL-18 and enhances innate lymphoid cell and T cell responses and parasite control, whereas IL-18BP-resistant DR-18 enhances CD4+ T cell IFN-γ but causes pathology.\",\n      \"method\": \"Mouse infection model, D2D IL-18 construct, DR-18 construct, flow cytometry, IFN-γ measurement, parasite burden quantification\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — engineered protein tools and in vivo genetic/pharmacological approaches with multiple readouts\",\n      \"pmids\": [\"36827187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-92b-5p directly suppresses IL-18BP expression in microglia; transfection with miR-92b-5p decreases IL-18BP and increases IL-18 mRNA, while miR-92b-5p inhibitor reverses this. In a mouse spinal cord injury model, miR-92b-5p inhibitor intrathecal injection increases IL-18BP and reduces inflammatory mediators (iNOS, TNF-α, IL-1β), improving locomotor function.\",\n      \"method\": \"miRNA transfection and inhibitor treatment in microglia, qRT-PCR, Western blot, in vivo spinal cord injury model, intrathecal injection, Basso Mouse Scale locomotor evaluation\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — in vitro and in vivo data connecting miR-92b-5p to IL-18BP regulation, single lab\",\n      \"pmids\": [\"30915731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-18BP alleviates HSR-induced anxiety-like behavior in mice by inhibiting the IL-18R-NLRP3 signaling pathway in astrocytes, reducing astrocytic activation, cleaved caspase-1, GSDMD, and pyroptosis-associated factors; these effects are partially reversed by the NLRP3 agonist nigericin and are absent in astrocyte-specific NLRP3 knockout mice.\",\n      \"method\": \"Mouse hemorrhagic shock/resuscitation model, IL-18BP intraperitoneal injection, open-field and elevated plus maze behavioral tests, Western blot (caspase-1, GSDMD), immunofluorescence, astrocyte-specific NLRP3 KO mice, NLRP3 agonist nigericin rescue experiment\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic rescue (NLRP3 KO) and pharmacological (nigericin) confirmation in vivo, single lab\",\n      \"pmids\": [\"36269543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Anti-IL-18BP monoclonal antibody (COM503) blocks the IL-18BP:IL-18 interaction and displaces pre-complexed IL-18, restoring free IL-18 activity and enhancing T- and NK-cell activation in vitro. In vivo, surrogate anti-IL-18BP induces tumor-localized immune modulation (increased polyfunctional non-exhausted T and NK cells) without systemic inflammatory cytokine elevation, demonstrating that IL-18BP sequestration in the TME is the primary mechanism suppressing IL-18.\",\n      \"method\": \"Anti-IL-18BP antibody generation, displacement assay for pre-complexed IL-18, T/NK cell activation in vitro assays, multiple syngeneic mouse tumor models, TME immune phenotyping by flow cytometry, serum cytokine measurement\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro displacement assay plus multiple in vivo tumor models with mechanistic TME analysis\",\n      \"pmids\": [\"38592331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In rainbow trout, recombinant IL-18BP functions as a decoy receptor that downregulates IL-18-induced NF-κB activation in HEK293T cells, demonstrating conserved inhibitory function. Co-IP assays showed IL-18Rβ forms a complex with MyD88, IRAK4, IRAK1, TRAF6, and TAB2, placing IL-18BP inhibition upstream of this signaling complex.\",\n      \"method\": \"Transfection of chimeric receptors in HEK293T cells, NF-κB reporter assay, co-immunoprecipitation\",\n      \"journal\": \"Developmental and comparative immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — functional assay plus Co-IP in a non-mammalian ortholog system, confirms conserved mechanism\",\n      \"pmids\": [\"36496012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-18BP (as APB-R3, an albumin-binding long-acting recombinant form) directly inactivates IL-18 and alleviates liver inflammation and splenomegaly in IL-18BP knockout mice with macrophage activation syndrome, and controls skin inflammation in atopic dermatitis, demonstrating that IL-18BP blockade of IL-18 is sufficient to suppress these inflammatory phenotypes.\",\n      \"method\": \"IL-18BP knockout mouse MAS model, APB-R3 treatment, liver and spleen pathology assessment, atopic dermatitis mouse model, pharmacokinetics measurement\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — IL-18BP KO mouse model plus pharmacological rescue provides direct mechanistic evidence\",\n      \"pmids\": [\"37918054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Il18bp KO mice, NK cells become inert upon mousepox infection and fail to activate or expand, resulting in viremic MAS and poor viral clearance, demonstrating that IL-18BP is required for proper NK cell function during viral infection and that its absence leads to NK cell hypoactivation alongside CTL hyperactivation.\",\n      \"method\": \"Il18bp knockout mice, mousepox infection model, NK cell transfer rescue experiment, CTL expansion and viral clearance assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with in vivo rescue by NK cell transfer; 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 decoy receptor (Kd ~400 pM, 1:1 stoichiometry) that binds mature IL-18 with a very slow off-rate to block its interaction with IL-18Rα/IL-18Rβ and downstream MyD88-IRAK-TRAF6-NF-κB/IFN-γ signaling; its expression is constitutive in liver and induced strongly by IFN-γ through direct STAT1 binding to a proximal GAS element in its promoter (with cell-type-specific epigenetic gating by CpG methylation in monocytes), creating a negative feedback loop; in vivo, IL-18BP deficiency unleashes NK cell-mediated hepatocyte killing and dysregulates the IL-18/NK/CTL axis during viral infection, while tumour-upregulated IL-18BP acts as an immune checkpoint that can be overcome by IL-18BP-resistant IL-18 variants or anti-IL-18BP antibodies.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL-18BP is a secreted high-affinity decoy receptor that neutralizes IL-18 by forming a 1:1 complex (Kd ~400 pM) with an extremely slow dissociation rate, thereby preventing IL-18 from engaging IL-18Rα/IL-18Rβ and blocking downstream MyD88–IRAK–TRAF6–NF-κB signaling and IFN-γ production [PMID:11497494, PMID:36496012]. Its transcription is induced by IFN-γ via direct STAT1 binding to a proximal GAS element in the IL-18BP promoter, creating a negative feedback loop, with cell-type-specific modulation by CpG methylation at a single site adjacent to the GAS element that silences expression in monocytes but not epithelial cells [PMID:19046253, PMID:29409936]. Homozygous loss-of-function mutations in IL18BP cause fulminant viral hepatitis through unrestrained IL-18-driven NK cell killing of hepatocytes [PMID:31213488]. In the tumor microenvironment, IL-18BP is upregulated as a secreted immune checkpoint that suppresses anti-tumor T and NK cell responses, an activity that can be overcome by decoy-resistant IL-18 variants or anti-IL-18BP antibodies that displace pre-complexed IL-18 [PMID:32581358, PMID:38592331].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"The existence of a soluble, non-receptor antagonist of IL-18 was unknown; affinity purification from human urine identified IL-18BP as a novel secreted protein homologous to viral IL-18-binding proteins that potently neutralizes IL-18 in vitro and in vivo, establishing a new class of cytokine regulation.\",\n      \"evidence\": \"IL-18 ligand affinity chromatography of concentrated human urine, protein microsequencing, cDNA cloning, recombinant protein neutralization assays\",\n      \"pmids\": [\"38455460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding affinity and stoichiometry not yet quantified\", \"Endogenous expression sites and regulation unknown\", \"Mechanism of action at the receptor level unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Quantitative binding parameters were established: IL-18BP forms a 1:1 complex with IL-18 at Kd ~400 pM with a very slow off-rate, and circulating levels rise ~10-fold in sepsis to sequester most free IL-18, resolving how the decoy functions stoichiometrically in vivo.\",\n      \"evidence\": \"Sandwich ELISA and electrochemiluminescence assay for IL-18BPa and IL-18 in healthy and sepsis sera, mass action law calculations\",\n      \"pmids\": [\"11497494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for high-affinity binding not determined\", \"Source tissues responsible for elevated circulating IL-18BP during inflammation unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The question of how IL-18BP is regulated during inflammation was addressed: LPS selectively induces IL-18BP but not IL-18 mRNA in liver, while IL-18BPa:Fc blocks LPS/IL-12-induced IFN-γ and MMP-9 from human blood, confirming IL-18BP as an endogenous brake on IL-18-mediated inflammation.\",\n      \"evidence\": \"Real-time PCR in rat liver after LPS, human whole blood culture with IL-18BPa:Fc and ELISA readout\",\n      \"pmids\": [\"12788303\", \"12907250\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor(s) driving LPS-induced IL-18BP expression unidentified\", \"In vivo pharmacokinetics of IL-18BPa:Fc not established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The transcriptional mechanism of IFN-γ-induced IL-18BP expression was dissected, showing that STAT1 binds directly to a proximal GAS element in the IL-18BP promoter independently of IRF-1, establishing the molecular basis for the IFN-γ–IL-18BP negative feedback loop.\",\n      \"evidence\": \"EMSA, ChIP for STAT1, promoter mutagenesis, siRNA knockdown in DLD-1 cells\",\n      \"pmids\": [\"19046253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Additional transcription factor cooperativity not fully explored\", \"Whether this GAS-dependent mechanism operates identically across all cell types unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Cell-type-specific epigenetic gating of IL-18BP induction was revealed: CpG methylation at a single site adjacent to the GAS element recruits MeCP2 and represses H3K9 acetylation and RNA Pol II loading in monocytes but not epithelial cells, explaining why monocytes are refractory to IFN-γ-driven IL-18BP expression. Separately, hepatic IL-18BP transcription was shown to require both STAT1 and C/EBPβ.\",\n      \"evidence\": \"Bisulfite sequencing, 5-aza-dC treatment, MeCP2 binding assay, H3K9ac and Pol II ChIP in monocytic vs. epithelial cells; luciferase reporter, ChIP, and siRNA rescue in hepatocytes\",\n      \"pmids\": [\"29409936\", \"30089853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CpG methylation is dynamically altered during monocyte differentiation or activation untested\", \"Full set of tissue-specific cofactors not catalogued\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The first human disease caused by IL-18BP deficiency was identified: a homozygous 40-nt deletion abolishing IL-18BP function led to fulminant hepatitis A, with unchecked IL-18-driven NK cell killing of hepatocytes, establishing IL-18BP as essential for hepatic immune homeostasis.\",\n      \"evidence\": \"Whole-exome sequencing of affected individual, loss-of-function validation, in vitro NK cell cytotoxicity assay against human hepatocytes, liver immunohistochemistry\",\n      \"pmids\": [\"31213488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other viral hepatitides are similarly gated by IL-18BP deficiency unknown\", \"Contribution of other IL-18BP isoforms not assessed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"IL-18BP was recognized as a tumor-associated immune checkpoint: tumors upregulate IL-18BP to neutralize IL-18 in the microenvironment, and a directed-evolution-derived decoy-resistant IL-18 (DR-18) bypasses IL-18BP, rescuing polyfunctional CD8+ T cells, reducing T cell exhaustion, and promoting NK cell maturation for anti-tumor immunity.\",\n      \"evidence\": \"Directed evolution of IL-18, multiple syngeneic mouse tumor models, flow cytometric T and NK cell phenotyping, transcriptional profiling\",\n      \"pmids\": [\"32581358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which tumors upregulate IL-18BP not defined\", \"Whether DR-18 causes systemic inflammatory toxicity in long-term models unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The in vivo role of IL-18BP during infection was further refined: a 'decoy-to-the-decoy' IL-18 construct that sequesters IL-18BP without signaling enhances innate lymphoid cell and T cell responses during Toxoplasma gondii infection, while IL-18BP knockout mice develop macrophage activation syndrome-like liver inflammation that is rescued by recombinant IL-18BP.\",\n      \"evidence\": \"D2D and DR-18 constructs in mouse infection models with flow cytometry and parasite burden; IL-18BP KO mouse MAS model with APB-R3 pharmacological rescue\",\n      \"pmids\": [\"36827187\", \"37918054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the D2D approach is applicable to other IL-18BP-dominant disease settings untested\", \"Long-term consequences of IL-18BP blockade on immune tolerance unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Therapeutic targeting of IL-18BP in tumors was validated: an anti-IL-18BP monoclonal antibody (COM503) displaces pre-complexed IL-18 and restores tumor-localized T and NK cell activation without systemic cytokine elevation, demonstrating that IL-18BP sequestration in the TME is the dominant mechanism suppressing anti-tumor IL-18 activity.\",\n      \"evidence\": \"Antibody displacement assay, T/NK cell activation in vitro, multiple syngeneic mouse tumor models, TME immune phenotyping, serum cytokine measurement\",\n      \"pmids\": [\"38592331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Efficacy in human tumors not yet demonstrated\", \"Structural basis of antibody-mediated IL-18 displacement from IL-18BP unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of the IL-18BP–IL-18 interaction at atomic resolution validated experimentally, the full catalogue of tissue- and disease-specific transcriptional and post-transcriptional regulators of IL-18BP, and whether IL-18BP has IL-18-independent functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimentally validated high-resolution structure of the human IL-18BP–IL-18 complex\", \"Post-translational modifications and secretion mechanism of IL-18BP uncharacterized\", \"Potential IL-18-independent roles of IL-18BP not investigated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 6, 12, 15]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0, 1, 6, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 5, 6, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 5, 6, 12, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 6, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IL18\",\n      \"STAT1\",\n      \"CEBPB\",\n      \"MECP2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}