{"gene":"IL18R1","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1996,"finding":"IL18R1 (IL-1Rrp) was identified as a novel IL-1 receptor family member whose cytoplasmic domain, when fused to the IL-1R extracellular/transmembrane regions, signals through NF-κB activation and IL-8 promoter induction in response to IL-1, demonstrating that the IL18R1 cytoplasmic domain is functionally competent for downstream signaling.","method":"Chimeric receptor transfection into COS cells, NF-κB reporter assay, IL-8 promoter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — functional reconstitution via chimeric receptor with defined signaling readout","pmids":["8626725"],"is_preprint":false},{"year":2001,"finding":"Functional IL-18 signaling requires both IL-18Rα and IL-18Rβ chains: COS-1 cells expressing IL-18Rα alone do not respond to IL-18, but transfection of IL-18Rβ cDNA reconstitutes IL-18-induced IL-8 and luciferase reporter activity; antibody blocking of IL-18Rα abolishes this response, establishing that both chains are necessary for a functional receptor complex.","method":"Transient transfection of IL-18Rβ cDNA into COS-1 cells, luciferase reporter assay, IL-8 measurement, anti-IL-18Rα blocking antibody","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — functional reconstitution in defined cell system with antibody validation","pmids":["11123287"],"is_preprint":false},{"year":2001,"finding":"IL-1H (a novel IL-1-related molecule) binds the IL-18 receptor but not the IL-1 receptor, identifying it as a second ligand for the IL-18R axis.","method":"Receptor binding assay using recombinant protein expressed in mammalian cells","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 3 — single binding assay without detailed mutagenesis or co-crystal structure","pmids":["11145836"],"is_preprint":false},{"year":2001,"finding":"IL-12 upregulates steady-state mRNA levels of both IL-18Rα and IL-18Rβ chains in NKO cells and PBMC, and IFN-γ production correlates with this IL-12-induced upregulation, indicating that IL-12 amplifies IL-18 signaling capacity by increasing receptor expression.","method":"RT-PCR/Northern blot for receptor mRNA, IFN-γ ELISA, NK cell line and PBMC stimulation assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — clean functional experiment with defined cellular readout, single lab","pmids":["11123287"],"is_preprint":false},{"year":2002,"finding":"IFN-γ regulates IL-18Rα expression during Th1 differentiation by counteracting the negative effects of IL-4 on IL-18Rα upregulation; in the absence of IL-4, IL-12-driven IL-18Rα upregulation is IFN-γ-independent, but in the presence of IL-4, IFN-γ is required to preserve IL-18Rα expression.","method":"T cell differentiation assays using IFN-γ-/- mice, IL-4 neutralization, flow cytometry for IL-18Rα surface expression","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout combined with neutralizing antibody, multiple orthogonal conditions tested","pmids":["12055229"],"is_preprint":false},{"year":2002,"finding":"A 3-base deletion splice variant (950delCAG) of the IL-18Rα chain cDNA is associated with reduced IFN-γ production in response to IL-18 stimulation, indicating that this alternative splicing event impairs receptor function.","method":"cDNA sequencing of IL-18Rα from atopic patients, PBMC IL-18 stimulation assays, IFN-γ measurement","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 — natural variant linked to functional deficit in primary cells","pmids":["11941317"],"is_preprint":false},{"year":2003,"finding":"A splice variant of IL-18Rβ encoding only the first immunoglobulin-like domain (predicted soluble truncated form) is expressed in rat brain regions and glial cells, and is rapidly upregulated in microglia by LPS, suggesting it acts as an endogenous regulator of IL-18 activity analogous to the soluble IL-1R accessory protein.","method":"RT-PCR identification of splice variant, cell-type-specific expression in purified microglia/astrocytes/neurons, LPS stimulation","journal":"Journal of neuroimmunology","confidence":"Medium","confidence_rationale":"Tier 2 — novel splice variant identified with cell-type specificity and stimulus-dependent regulation, but functional consequence is inferred","pmids":["14644029"],"is_preprint":false},{"year":2003,"finding":"TNF-α and H2O2 induce IL-18Rβ (but not IL-18Rα) expression in cardiomyocytes via NF-κB activation, as demonstrated by PDTC (NF-κB inhibitor) blocking of agonist-induced IL-18Rβ expression while not affecting basal IL-18Rα expression.","method":"NF-κB activation assays, mRNA/protein expression analysis, PDTC inhibitor treatment in primary cardiomyocytes","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological inhibitor with defined pathway readout in primary cells","pmids":["12684057"],"is_preprint":false},{"year":2003,"finding":"IL-18R is expressed on human dendritic cells and IFN-γ upregulates its surface expression on monocyte-derived DCs; IL-18 directly induces filamentous actin polymerization and DC migration in Boyden chamber assays, demonstrating a chemoattractant function of IL-18/IL-18R signaling on DCs.","method":"Flow cytometry for IL-18R expression, IFN-γ stimulation, filamentous actin staining, Boyden chamber migration assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional migration assay with actin polymerization readout, single lab","pmids":["14662834"],"is_preprint":false},{"year":2008,"finding":"Transcription factor GATA-3 binds to the Il18r1 locus at conserved non-coding sequences overlapping with DNase hypersensitivity sites, and ectopic GATA-3 expression in differentiated Th1 cells represses Il18r1 mRNA and surface expression of IL-18Rα; Stat6 is required for Il18r1 repression during Th2 differentiation.","method":"Chromatin remodeling (DNase hypersensitivity assay), ChIP for GATA-3 and Stat6, histone modification analysis, ectopic GATA-3 expression, Stat6-/- mice","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP, genetic knockout, ectopic expression, and chromatin assays in single study","pmids":["18714006"],"is_preprint":false},{"year":2013,"finding":"IL-18R subunits (IL-18Rα and IL-18Rβ) physically associate with Nox1 under basal conditions, and IL-18 stimulation enhances this IL-18R/Nox1 binding; this complex drives Nox1-dependent ROS generation leading to TRAF3IP2 induction and IKK/NF-κB and JNK/AP-1 activation in human coronary artery smooth muscle cells, mediating IL-18-induced SMC migration.","method":"Co-immunoprecipitation, GST pull-down, Nox1 ROS assay, NF-κB/AP-1 reporter assays, migration assay","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1-2 — Co-IP and GST pull-down demonstrating physical association, combined with functional migration assay","pmids":["23541442"],"is_preprint":false},{"year":2014,"finding":"IL-18 induces its own expression and that of IL-18Rα via AP-1 activation, and promotes cardiomyocyte hypertrophy in part via PI3K/Akt/GATA4 signaling; cyclical mechanical stretch enhances ANP, IL-18, and IL-18Rα expression in primary rabbit cardiomyocytes.","method":"Primary rabbit cardiomyocyte culture, cyclic stretch model, rabbit IL-18Rα cDNA cloning, AP-1 reporter, PI3K/Akt/GATA4 pathway inhibitors","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 — signaling pathway defined with pharmacological inhibitors in primary cells","pmids":["25108227"],"is_preprint":false},{"year":2017,"finding":"T cell-intrinsic IL-18R and MyD88 signaling are required for Th1 cell proliferation, protection from apoptosis, and expression of activation/memory genes during Trypanosoma cruzi infection; Il18r1-deficient mice exhibit lower Th1 cell levels and higher susceptibility to infection, rescued by adoptive transfer of WT CD4+ T cells, establishing IL-18R/MyD88 as a critical T cell-intrinsic pathway for cognate Th1 responses.","method":"Mixed bone marrow chimeras, transcriptome analysis, cytometry, Il18r1-/- mice, adoptive transfer rescue experiment","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout, mixed chimeras, transcriptomics, and adoptive transfer rescue across multiple orthogonal approaches","pmids":["28895840"],"is_preprint":false},{"year":2017,"finding":"CD4 Th1 cell expression of both IL-18R and DR3 (but not IL-15R) is required for optimal TCR-independent (non-cognate) IFN-γ induction in Salmonella-infected mice; T cell-intrinsic MyD88 deficiency increases bacterial burden in Salmonella, Chlamydia, and Brucella infections.","method":"Knockout mouse models for IL-18R, DR3, IL-15R, and MyD88; intracellular IFN-γ staining; bacterial burden measurements","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 — multiple receptor knockouts with defined functional readout across three pathogens","pmids":["28817719"],"is_preprint":false},{"year":2020,"finding":"IL-18R signaling is intrinsically required in γδ T cells for their proliferation, generation of cytotoxic GzB+ and IFN-γ-producing γδ T cells, and protection against T. cruzi infection; adoptive transfer of WT γδ T cells rescues Il18r1-/- mice from susceptibility.","method":"Il18r1-/- and Myd88-/- mice, in vivo/in vitro proliferation assays, intracellular cytokine staining, adoptive transfer","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout, adoptive transfer rescue, in vitro and in vivo validation","pmids":["32450614"],"is_preprint":false},{"year":2021,"finding":"IL-18R signaling is cell-intrinsically required for short-term HSC quiescence (but not for HSPC cell death) during severe infection; IFN-αβ promote IL-18 expression, which through IL-18R drives ST-HSC quiescence, contributing to bone marrow aplasia.","method":"Il18r1-/- mice, Il18-/- mice, Ixodes ovatus Ehrlichia infection model, flow cytometry, bone marrow transplantation assays","journal":"Stem cell reports","confidence":"High","confidence_rationale":"Tier 2 — genetic knockouts with cell-intrinsic dissection of quiescence vs. death phenotypes","pmids":["34798063"],"is_preprint":false},{"year":2021,"finding":"Downregulation of IL-18R expression marks bona fide tissue-resident (Trm) CD8+ T cells in the kidney; TGF-β and IFN-α/β, and TGF-β-dependent suppression of Tcf-1, are required for IL-18R downregulation during kidney Trm differentiation, as demonstrated by parabiosis and transcriptional analysis.","method":"Parabiosis experiments, global transcriptional analysis (scRNA-seq), flow cytometry, cytokine blocking/knockout, Tcf-1 reporter","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 — parabiosis plus transcriptomics plus cytokine pathway dissection with multiple orthogonal approaches","pmids":["33474536"],"is_preprint":false},{"year":2022,"finding":"CD4+ cytotoxic T cell (CD4CTL) differentiation and function during T. cruzi infection require T cell-intrinsic IL-18R/MyD88 signaling; Il18ra-/- and Myd88-/- CD4+ T cells phenocopy each other in mixed bone marrow chimeras, and adoptive transfer of WT CD4+GzB+ T cells to infected Il18ra-/- mice extends survival.","method":"Mixed bone marrow chimeras, Il18ra-/- and Myd88-/- mice, adoptive transfer, cytotoxicity assays, single-cell transcriptomics","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — mixed chimeras, genetic knockouts phenocopying each other, adoptive transfer rescue, multiple orthogonal methods","pmids":["35670567"],"is_preprint":false},{"year":2022,"finding":"IL18/IL18R1 signaling promotes NF-κB nuclear entry and activates the HIF-1 signaling pathway in macrophages, as shown by proteomic analysis; macrophage-derived IL-18 acting through IL18R1 promotes M1 macrophage polarization and synthetic phenotype transformation of vascular smooth muscle cells.","method":"Intercellular communication analysis (scRNA-seq), proteomic analysis, pseudo-time analysis, VIPER analysis","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 3 — multi-omics computational analysis with proteomic validation, no direct in vitro reconstitution","pmids":["35069552"],"is_preprint":false},{"year":2022,"finding":"IL-18/IL-18R signaling in IL-18R+ NK cells and T cells drives IFN-γ production, which in turn stimulates ROS-mediated bactericidal activity in neutrophils, restricting Legionella longbeachae infection; this IL-18R/IFN-γ/ROS axis was defined using cell ablation experiments and IL-18 deficiency.","method":"Cell type ablation, IL-18R expression profiling, IL-18-deficient mice, ROS measurement, IFN-γ assays, infection model","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic deficiency and cell ablation defining pathway axis, single study","pmids":["38750967"],"is_preprint":false},{"year":2022,"finding":"IL-18R signaling prevents IL-17A production from ILC2s in the lung during fungal allergen exposure; in IL-18R-/- mice, both ST2+ and ST2-negative ILCs show increased IL-17A production and enhanced lung eosinophilia, with IL-18 expressed by alveolar macrophages acting on IL-13+ILC2s expressing IL-18R.","method":"IL-18R-/- mice, Alternaria alternata challenge model, scRNA-seq, flow cytometry, cytokine production assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockout with scRNA-seq and defined functional phenotype, but preprint","pmids":["40777291"],"is_preprint":true},{"year":2022,"finding":"IL-18/IL-18R signaling suppresses the growth of ILC precursors (ILCPs) and ILCs by inhibiting proliferation and inducing apoptosis under elevated IL-18 conditions; Il18r1-deficient lymphoid progenitors can still generate all ILC subsets, indicating IL-18R is not required for ILC lineage commitment but constrains ILC expansion.","method":"Il18r1-/- and Il18-/- mice, in vitro differentiation assay, adoptive transfer, single-cell gene expression analysis","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic knockouts with multiple functional readouts (proliferation, apoptosis, differentiation) across in vitro and in vivo models","pmids":["35874724"],"is_preprint":false}],"current_model":"IL18R1 (IL-18Rα) forms a heterodimeric receptor complex with IL-18Rβ that is required for IL-18 signal transduction; ligand binding to IL-18Rα alone is insufficient for signaling, but co-expression of IL-18Rβ reconstitutes NF-κB/AP-1 activation, cytokine production, and downstream effects including cell migration; the receptor complex physically associates with Nox1 to generate ROS, activates PI3K/Akt/GATA4 and NF-κB/JNK pathways in various cell types, and through T cell-intrinsic MyD88 signaling drives Th1, CD4CTL, and γδ T cell responses against intracellular pathogens; IL-18Rα expression is transcriptionally regulated by GATA-3 (repression) and Stat6 during Th1/Th2 differentiation, and its downregulation marks kidney tissue-resident CD8+ T cells through TGF-β/IFN-αβ-dependent suppression of Tcf-1."},"narrative":{"teleology":[{"year":1996,"claim":"Before its ligand was known, the identification of IL18R1 as a novel IL-1R family member whose cytoplasmic domain could activate NF-κB established that this orphan receptor possessed intrinsic signaling competence through the TIR domain.","evidence":"Chimeric receptor (IL-1R ectodomain/IL18R1 cytoplasmic domain) transfected into COS cells with NF-κB and IL-8 promoter reporter assays","pmids":["8626725"],"confidence":"High","gaps":["Cognate ligand not yet identified","Accessory chain requirement unknown","Downstream adaptor molecules not defined"]},{"year":2001,"claim":"The requirement for a heterodimeric receptor was resolved when reconstitution showed that IL-18Rα alone binds IL-18 but cannot signal, and co-expression of IL-18Rβ restores IL-18-dependent NF-κB activation and cytokine induction.","evidence":"COS-1 transfection of IL-18Rβ cDNA, luciferase reporter, IL-8 ELISA, anti-IL-18Rα blocking antibody","pmids":["11123287"],"confidence":"High","gaps":["Structural basis of α/β heterodimerization not determined","Stoichiometry of receptor complex not addressed","Identity of a second IL-18R ligand (IL-1H) only preliminarily characterized"]},{"year":2002,"claim":"IL-18Rα expression was shown to be dynamically regulated during Th1/Th2 differentiation: IL-12 upregulates both receptor chains, while IL-4 suppresses IL-18Rα unless IFN-γ counteracts, establishing IL-18Rα surface levels as a checkpoint in T helper lineage commitment.","evidence":"T cell differentiation using IFN-γ−/− mice, IL-4 neutralization, flow cytometry for surface IL-18Rα","pmids":["12055229","11123287"],"confidence":"High","gaps":["Cis-regulatory elements governing IL-18Rα transcription not mapped","Direct versus indirect effects of IFN-γ on IL-18Rα promoter not resolved"]},{"year":2003,"claim":"Beyond immune signaling, IL-18R was found to mediate direct cell motility: IL-18 induces actin polymerization and chemotaxis in dendritic cells, and NF-κB-dependent IL-18Rβ upregulation in cardiomyocytes established the receptor's role outside classical lymphoid compartments.","evidence":"Boyden chamber migration assay and F-actin staining on monocyte-derived DCs; NF-κB inhibitor (PDTC) treatment in primary cardiomyocytes","pmids":["14662834","12684057"],"confidence":"Medium","gaps":["Signaling intermediates linking IL-18R to actin remodeling not identified","In vivo relevance of DC migration via IL-18R not tested"]},{"year":2008,"claim":"The transcriptional basis of IL-18Rα silencing in Th2 cells was defined: GATA-3 directly binds the Il18r1 locus at conserved non-coding regions and represses transcription, and this repression requires Stat6, linking IL-4/Stat6/GATA-3 to chromatin-level control of IL-18 responsiveness.","evidence":"ChIP for GATA-3, DNase hypersensitivity assay, ectopic GATA-3 in Th1 cells, Stat6−/− mice","pmids":["18714006"],"confidence":"High","gaps":["Precise enhancer-promoter architecture of the Il18r1 locus not resolved","Whether GATA-3-mediated repression is reversible in committed Th2 cells not tested"]},{"year":2013,"claim":"The discovery that IL-18Rα/β physically associates with Nox1 and that IL-18 enhances this interaction revealed a proximal ROS-generating mechanism upstream of NF-κB/JNK and TRAF3IP2, explaining how IL-18R drives smooth muscle cell migration.","evidence":"Co-immunoprecipitation and GST pull-down for IL-18R/Nox1 association; Nox1 ROS assay, NF-κB/AP-1 reporters, and migration assay in human coronary artery SMCs","pmids":["23541442"],"confidence":"High","gaps":["Binding interface between IL-18R and Nox1 not mapped","Whether IL-18R/Nox1 complex forms in other cell types not tested"]},{"year":2017,"claim":"Using mixed bone marrow chimeras and adoptive transfer rescue, IL-18R/MyD88 was established as a T cell-intrinsic signaling axis essential for Th1 proliferation, survival, and host protection against intracellular pathogens (T. cruzi, Salmonella, Chlamydia, Brucella).","evidence":"Il18r1−/− and Myd88−/− mixed chimeras, transcriptomics, adoptive transfer of WT CD4+ T cells, multiple intracellular pathogen infection models","pmids":["28895840","28817719"],"confidence":"High","gaps":["Specific MyD88-dependent transcriptional targets downstream of IL-18R in T cells not fully cataloged","Whether IL-18R signals through IRAK kinases in T cells not directly shown"]},{"year":2020,"claim":"IL-18R/MyD88 signaling was shown to be intrinsically required not only in CD4+ T cells but also in γδ T cells for their proliferation and cytotoxic effector function during T. cruzi infection, broadening the receptor's role to unconventional T cell subsets.","evidence":"Il18r1−/− mice, adoptive transfer of WT γδ T cells rescuing susceptibility, intracellular cytokine staining","pmids":["32450614"],"confidence":"High","gaps":["Molecular basis of IL-18R regulation of granzyme B expression in γδ T cells not defined","Whether IL-18R signaling differs mechanistically in γδ versus αβ T cells not addressed"]},{"year":2021,"claim":"Two new biological contexts for IL-18R were established: cell-intrinsic IL-18R signaling drives hematopoietic stem cell quiescence during severe infection, and downregulation of IL-18R via TGF-β/IFN-αβ/Tcf-1 suppression marks kidney tissue-resident CD8+ T cells.","evidence":"Il18r1−/− mice in Ehrlichia infection for HSC quiescence; parabiosis, scRNA-seq, and cytokine pathway dissection for kidney Trm","pmids":["34798063","33474536"],"confidence":"High","gaps":["Mechanism by which IL-18R enforces HSC quiescence (cell cycle arrest pathway) not identified","Whether IL-18R downregulation is a universal Trm marker across tissues not determined"]},{"year":2022,"claim":"IL-18R/MyD88 was identified as the critical T cell-intrinsic pathway for CD4 cytotoxic T lymphocyte (CD4CTL) differentiation, with Il18r1−/− and Myd88−/− CD4+ T cells phenocopying each other in mixed chimeras, and IL-18R signaling was separately shown to constrain ILC expansion by inhibiting proliferation and inducing apoptosis.","evidence":"Mixed bone marrow chimeras, adoptive transfer of GzB+ CD4+ T cells, single-cell transcriptomics for CD4CTL; Il18r1−/− and Il18−/− mice with in vitro ILC differentiation and adoptive transfer for ILC function","pmids":["35670567","35874724"],"confidence":"High","gaps":["Epigenetic programs downstream of IL-18R that commit CD4 cells to cytotoxic fate not mapped","Whether IL-18R-mediated ILC apoptosis is caspase-dependent not tested"]},{"year":null,"claim":"Key unresolved questions include the structural basis of IL-18Rα/IL-18Rβ heterodimerization, the full spectrum of adaptor complexes recruited to the IL-18R TIR domain in different cell types, and whether IL-18R signals through distinct downstream pathways in hematopoietic stem cells versus lymphocytes.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of the IL-18/IL-18Rα/IL-18Rβ signaling complex","IRAK recruitment to IL-18R TIR domain not directly demonstrated","Cell-type-specific signaling outputs downstream of IL-18R not systematically compared"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10,12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,4,8]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12,13,14,17,19,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,10,11,18]}],"complexes":["IL-18Rα/IL-18Rβ heterodimer","IL-18R/Nox1 complex"],"partners":["IL18RAP","NOX1","MYD88","GATA3","TRAF3IP2","IL18"],"other_free_text":[]},"mechanistic_narrative":"IL18R1 (IL-18Rα) is the ligand-binding subunit of the heterodimeric IL-18 receptor complex, which transduces signals from IL-18 to drive innate and adaptive immune responses, inflammatory cell migration, and hematopoietic stem cell quiescence. IL-18Rα alone binds IL-18 but requires co-expression of IL-18Rβ to activate downstream NF-κB, AP-1, JNK, and PI3K/Akt signaling, with the receptor complex physically associating with Nox1 to generate ROS that amplify these cascades [PMID:11123287, PMID:23541442]. T cell-intrinsic IL-18R/MyD88 signaling is essential for Th1 proliferation, CD4 cytotoxic T cell differentiation, and γδ T cell effector function during intracellular pathogen infection, and also constrains ILC expansion by inhibiting proliferation and inducing apoptosis [PMID:28895840, PMID:35670567, PMID:32450614, PMID:35874724]. IL18R1 transcription is repressed by GATA-3 and Stat6 during Th2 differentiation, and its downregulation via TGF-β/IFN-αβ-dependent suppression of Tcf-1 marks kidney tissue-resident CD8+ T cells [PMID:18714006, PMID:33474536]."},"prefetch_data":{"uniprot":{"accession":"Q13478","full_name":"Interleukin-18 receptor 1","aliases":["CD218 antigen-like family member A","CDw218a","IL1 receptor-related protein","IL-1Rrp","IL1R-rp","Interleukin-18 receptor alpha","IL-18R-alpha","IL-18Ralpha"],"length_aa":541,"mass_kda":62.3,"function":"Within the IL18 receptor complex, responsible for the binding of the pro-inflammatory cytokine IL18, but not IL1A nor IL1B (PubMed:14528293, PubMed:25261253, PubMed:25500532, PubMed:37993714, PubMed:8626725). Involved in IL18-mediated IFNG synthesis from T-helper 1 (Th1) cells (PubMed:10653850). Contributes to IL18-induced cytokine production, either independently of SLC12A3, or as a complex with SLC12A3 (By similarity)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q13478/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL18R1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL18R1","total_profiled":1310},"omim":[{"mim_id":"612006","title":"CELIAC DISEASE, SUSCEPTIBILITY TO, 8; CELIAC8","url":"https://www.omim.org/entry/612006"},{"mim_id":"609888","title":"LEPROSY, SUSCEPTIBILITY TO, 1; LPRS1","url":"https://www.omim.org/entry/609888"},{"mim_id":"604512","title":"INTERLEUKIN 1 RECEPTOR-LIKE 2; IL1RL2","url":"https://www.omim.org/entry/604512"},{"mim_id":"604509","title":"INTERLEUKIN 18 RECEPTOR ACCESSORY PROTEIN; IL18RAP","url":"https://www.omim.org/entry/604509"},{"mim_id":"604494","title":"INTERLEUKIN 18 RECEPTOR 1; IL18R1","url":"https://www.omim.org/entry/604494"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lung","ntpm":11.3}],"url":"https://www.proteinatlas.org/search/IL18R1"},"hgnc":{"alias_symbol":["IL-18R","IL1RRP","IL-1Rrp","CD218a"],"prev_symbol":[]},"alphafold":{"accession":"Q13478","domains":[{"cath_id":"2.60.40.10","chopping":"28-44_53-113","consensus_level":"high","plddt":87.1901,"start":28,"end":113},{"cath_id":"2.60.40.10","chopping":"123-208","consensus_level":"high","plddt":92.2538,"start":123,"end":208},{"cath_id":"2.60.40.10","chopping":"217-316","consensus_level":"high","plddt":91.1247,"start":217,"end":316},{"cath_id":"3.40.50.10140","chopping":"363-520","consensus_level":"high","plddt":71.1397,"start":363,"end":520}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13478","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13478-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13478-F1-predicted_aligned_error_v6.png","plddt_mean":79.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL18R1","jax_strain_url":"https://www.jax.org/strain/search?query=IL18R1"},"sequence":{"accession":"Q13478","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13478.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13478/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13478"}},"corpus_meta":[{"pmid":"8626725","id":"PMC_8626725","title":"IL-1Rrp is a novel receptor-like molecule similar to the type I interleukin-1 receptor and its homologues T1/ST2 and IL-1R AcP.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8626725","citation_count":197,"is_preprint":false},{"pmid":"11145836","id":"PMC_11145836","title":"IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp.","date":"2001","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/11145836","citation_count":169,"is_preprint":false},{"pmid":"12055229","id":"PMC_12055229","title":"Role of IFN-gamma in Th1 differentiation: IFN-gamma regulates IL-18R alpha expression by preventing the negative effects of IL-4 and by inducing/maintaining IL-12 receptor beta 2 expression.","date":"2002","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/12055229","citation_count":103,"is_preprint":false},{"pmid":"10191101","id":"PMC_10191101","title":"Interleukin-1 receptor 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transfection into COS cells, NF-κB reporter assay, IL-8 promoter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional reconstitution via chimeric receptor with defined signaling readout\",\n      \"pmids\": [\"8626725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Functional IL-18 signaling requires both IL-18Rα and IL-18Rβ chains: COS-1 cells expressing IL-18Rα alone do not respond to IL-18, but transfection of IL-18Rβ cDNA reconstitutes IL-18-induced IL-8 and luciferase reporter activity; antibody blocking of IL-18Rα abolishes this response, establishing that both chains are necessary for a functional receptor complex.\",\n      \"method\": \"Transient transfection of IL-18Rβ cDNA into COS-1 cells, luciferase reporter assay, IL-8 measurement, anti-IL-18Rα blocking antibody\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional reconstitution in defined cell system with antibody validation\",\n      \"pmids\": [\"11123287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-1H (a novel IL-1-related molecule) binds the IL-18 receptor but not the IL-1 receptor, identifying it as a second ligand for the IL-18R axis.\",\n      \"method\": \"Receptor binding assay using recombinant protein expressed in mammalian cells\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single binding assay without detailed mutagenesis or co-crystal structure\",\n      \"pmids\": [\"11145836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-12 upregulates steady-state mRNA levels of both IL-18Rα and IL-18Rβ chains in NKO cells and PBMC, and IFN-γ production correlates with this IL-12-induced upregulation, indicating that IL-12 amplifies IL-18 signaling capacity by increasing receptor expression.\",\n      \"method\": \"RT-PCR/Northern blot for receptor mRNA, IFN-γ ELISA, NK cell line and PBMC stimulation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean functional experiment with defined cellular readout, single lab\",\n      \"pmids\": [\"11123287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IFN-γ regulates IL-18Rα expression during Th1 differentiation by counteracting the negative effects of IL-4 on IL-18Rα upregulation; in the absence of IL-4, IL-12-driven IL-18Rα upregulation is IFN-γ-independent, but in the presence of IL-4, IFN-γ is required to preserve IL-18Rα expression.\",\n      \"method\": \"T cell differentiation assays using IFN-γ-/- mice, IL-4 neutralization, flow cytometry for IL-18Rα surface expression\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout combined with neutralizing antibody, multiple orthogonal conditions tested\",\n      \"pmids\": [\"12055229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A 3-base deletion splice variant (950delCAG) of the IL-18Rα chain cDNA is associated with reduced IFN-γ production in response to IL-18 stimulation, indicating that this alternative splicing event impairs receptor function.\",\n      \"method\": \"cDNA sequencing of IL-18Rα from atopic patients, PBMC IL-18 stimulation assays, IFN-γ measurement\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — natural variant linked to functional deficit in primary cells\",\n      \"pmids\": [\"11941317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A splice variant of IL-18Rβ encoding only the first immunoglobulin-like domain (predicted soluble truncated form) is expressed in rat brain regions and glial cells, and is rapidly upregulated in microglia by LPS, suggesting it acts as an endogenous regulator of IL-18 activity analogous to the soluble IL-1R accessory protein.\",\n      \"method\": \"RT-PCR identification of splice variant, cell-type-specific expression in purified microglia/astrocytes/neurons, LPS stimulation\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — novel splice variant identified with cell-type specificity and stimulus-dependent regulation, but functional consequence is inferred\",\n      \"pmids\": [\"14644029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TNF-α and H2O2 induce IL-18Rβ (but not IL-18Rα) expression in cardiomyocytes via NF-κB activation, as demonstrated by PDTC (NF-κB inhibitor) blocking of agonist-induced IL-18Rβ expression while not affecting basal IL-18Rα expression.\",\n      \"method\": \"NF-κB activation assays, mRNA/protein expression analysis, PDTC inhibitor treatment in primary cardiomyocytes\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibitor with defined pathway readout in primary cells\",\n      \"pmids\": [\"12684057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IL-18R is expressed on human dendritic cells and IFN-γ upregulates its surface expression on monocyte-derived DCs; IL-18 directly induces filamentous actin polymerization and DC migration in Boyden chamber assays, demonstrating a chemoattractant function of IL-18/IL-18R signaling on DCs.\",\n      \"method\": \"Flow cytometry for IL-18R expression, IFN-γ stimulation, filamentous actin staining, Boyden chamber migration assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional migration assay with actin polymerization readout, single lab\",\n      \"pmids\": [\"14662834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Transcription factor GATA-3 binds to the Il18r1 locus at conserved non-coding sequences overlapping with DNase hypersensitivity sites, and ectopic GATA-3 expression in differentiated Th1 cells represses Il18r1 mRNA and surface expression of IL-18Rα; Stat6 is required for Il18r1 repression during Th2 differentiation.\",\n      \"method\": \"Chromatin remodeling (DNase hypersensitivity assay), ChIP for GATA-3 and Stat6, histone modification analysis, ectopic GATA-3 expression, Stat6-/- mice\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP, genetic knockout, ectopic expression, and chromatin assays in single study\",\n      \"pmids\": [\"18714006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-18R subunits (IL-18Rα and IL-18Rβ) physically associate with Nox1 under basal conditions, and IL-18 stimulation enhances this IL-18R/Nox1 binding; this complex drives Nox1-dependent ROS generation leading to TRAF3IP2 induction and IKK/NF-κB and JNK/AP-1 activation in human coronary artery smooth muscle cells, mediating IL-18-induced SMC migration.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, Nox1 ROS assay, NF-κB/AP-1 reporter assays, migration assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Co-IP and GST pull-down demonstrating physical association, combined with functional migration assay\",\n      \"pmids\": [\"23541442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-18 induces its own expression and that of IL-18Rα via AP-1 activation, and promotes cardiomyocyte hypertrophy in part via PI3K/Akt/GATA4 signaling; cyclical mechanical stretch enhances ANP, IL-18, and IL-18Rα expression in primary rabbit cardiomyocytes.\",\n      \"method\": \"Primary rabbit cardiomyocyte culture, cyclic stretch model, rabbit IL-18Rα cDNA cloning, AP-1 reporter, PI3K/Akt/GATA4 pathway inhibitors\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — signaling pathway defined with pharmacological inhibitors in primary cells\",\n      \"pmids\": [\"25108227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"T cell-intrinsic IL-18R and MyD88 signaling are required for Th1 cell proliferation, protection from apoptosis, and expression of activation/memory genes during Trypanosoma cruzi infection; Il18r1-deficient mice exhibit lower Th1 cell levels and higher susceptibility to infection, rescued by adoptive transfer of WT CD4+ T cells, establishing IL-18R/MyD88 as a critical T cell-intrinsic pathway for cognate Th1 responses.\",\n      \"method\": \"Mixed bone marrow chimeras, transcriptome analysis, cytometry, Il18r1-/- mice, adoptive transfer rescue experiment\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout, mixed chimeras, transcriptomics, and adoptive transfer rescue across multiple orthogonal approaches\",\n      \"pmids\": [\"28895840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD4 Th1 cell expression of both IL-18R and DR3 (but not IL-15R) is required for optimal TCR-independent (non-cognate) IFN-γ induction in Salmonella-infected mice; T cell-intrinsic MyD88 deficiency increases bacterial burden in Salmonella, Chlamydia, and Brucella infections.\",\n      \"method\": \"Knockout mouse models for IL-18R, DR3, IL-15R, and MyD88; intracellular IFN-γ staining; bacterial burden measurements\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple receptor knockouts with defined functional readout across three pathogens\",\n      \"pmids\": [\"28817719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-18R signaling is intrinsically required in γδ T cells for their proliferation, generation of cytotoxic GzB+ and IFN-γ-producing γδ T cells, and protection against T. cruzi infection; adoptive transfer of WT γδ T cells rescues Il18r1-/- mice from susceptibility.\",\n      \"method\": \"Il18r1-/- and Myd88-/- mice, in vivo/in vitro proliferation assays, intracellular cytokine staining, adoptive transfer\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout, adoptive transfer rescue, in vitro and in vivo validation\",\n      \"pmids\": [\"32450614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-18R signaling is cell-intrinsically required for short-term HSC quiescence (but not for HSPC cell death) during severe infection; IFN-αβ promote IL-18 expression, which through IL-18R drives ST-HSC quiescence, contributing to bone marrow aplasia.\",\n      \"method\": \"Il18r1-/- mice, Il18-/- mice, Ixodes ovatus Ehrlichia infection model, flow cytometry, bone marrow transplantation assays\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockouts with cell-intrinsic dissection of quiescence vs. death phenotypes\",\n      \"pmids\": [\"34798063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Downregulation of IL-18R expression marks bona fide tissue-resident (Trm) CD8+ T cells in the kidney; TGF-β and IFN-α/β, and TGF-β-dependent suppression of Tcf-1, are required for IL-18R downregulation during kidney Trm differentiation, as demonstrated by parabiosis and transcriptional analysis.\",\n      \"method\": \"Parabiosis experiments, global transcriptional analysis (scRNA-seq), flow cytometry, cytokine blocking/knockout, Tcf-1 reporter\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — parabiosis plus transcriptomics plus cytokine pathway dissection with multiple orthogonal approaches\",\n      \"pmids\": [\"33474536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD4+ cytotoxic T cell (CD4CTL) differentiation and function during T. cruzi infection require T cell-intrinsic IL-18R/MyD88 signaling; Il18ra-/- and Myd88-/- CD4+ T cells phenocopy each other in mixed bone marrow chimeras, and adoptive transfer of WT CD4+GzB+ T cells to infected Il18ra-/- mice extends survival.\",\n      \"method\": \"Mixed bone marrow chimeras, Il18ra-/- and Myd88-/- mice, adoptive transfer, cytotoxicity assays, single-cell transcriptomics\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mixed chimeras, genetic knockouts phenocopying each other, adoptive transfer rescue, multiple orthogonal methods\",\n      \"pmids\": [\"35670567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL18/IL18R1 signaling promotes NF-κB nuclear entry and activates the HIF-1 signaling pathway in macrophages, as shown by proteomic analysis; macrophage-derived IL-18 acting through IL18R1 promotes M1 macrophage polarization and synthetic phenotype transformation of vascular smooth muscle cells.\",\n      \"method\": \"Intercellular communication analysis (scRNA-seq), proteomic analysis, pseudo-time analysis, VIPER analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — multi-omics computational analysis with proteomic validation, no direct in vitro reconstitution\",\n      \"pmids\": [\"35069552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-18/IL-18R signaling in IL-18R+ NK cells and T cells drives IFN-γ production, which in turn stimulates ROS-mediated bactericidal activity in neutrophils, restricting Legionella longbeachae infection; this IL-18R/IFN-γ/ROS axis was defined using cell ablation experiments and IL-18 deficiency.\",\n      \"method\": \"Cell type ablation, IL-18R expression profiling, IL-18-deficient mice, ROS measurement, IFN-γ assays, infection model\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic deficiency and cell ablation defining pathway axis, single study\",\n      \"pmids\": [\"38750967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-18R signaling prevents IL-17A production from ILC2s in the lung during fungal allergen exposure; in IL-18R-/- mice, both ST2+ and ST2-negative ILCs show increased IL-17A production and enhanced lung eosinophilia, with IL-18 expressed by alveolar macrophages acting on IL-13+ILC2s expressing IL-18R.\",\n      \"method\": \"IL-18R-/- mice, Alternaria alternata challenge model, scRNA-seq, flow cytometry, cytokine production assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with scRNA-seq and defined functional phenotype, but preprint\",\n      \"pmids\": [\"40777291\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-18/IL-18R signaling suppresses the growth of ILC precursors (ILCPs) and ILCs by inhibiting proliferation and inducing apoptosis under elevated IL-18 conditions; Il18r1-deficient lymphoid progenitors can still generate all ILC subsets, indicating IL-18R is not required for ILC lineage commitment but constrains ILC expansion.\",\n      \"method\": \"Il18r1-/- and Il18-/- mice, in vitro differentiation assay, adoptive transfer, single-cell gene expression analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockouts with multiple functional readouts (proliferation, apoptosis, differentiation) across in vitro and in vivo models\",\n      \"pmids\": [\"35874724\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL18R1 (IL-18Rα) forms a heterodimeric receptor complex with IL-18Rβ that is required for IL-18 signal transduction; ligand binding to IL-18Rα alone is insufficient for signaling, but co-expression of IL-18Rβ reconstitutes NF-κB/AP-1 activation, cytokine production, and downstream effects including cell migration; the receptor complex physically associates with Nox1 to generate ROS, activates PI3K/Akt/GATA4 and NF-κB/JNK pathways in various cell types, and through T cell-intrinsic MyD88 signaling drives Th1, CD4CTL, and γδ T cell responses against intracellular pathogens; IL-18Rα expression is transcriptionally regulated by GATA-3 (repression) and Stat6 during Th1/Th2 differentiation, and its downregulation marks kidney tissue-resident CD8+ T cells through TGF-β/IFN-αβ-dependent suppression of Tcf-1.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL18R1 (IL-18Rα) is the ligand-binding subunit of the heterodimeric IL-18 receptor complex, which transduces signals from IL-18 to drive innate and adaptive immune responses, inflammatory cell migration, and hematopoietic stem cell quiescence. IL-18Rα alone binds IL-18 but requires co-expression of IL-18Rβ to activate downstream NF-κB, AP-1, JNK, and PI3K/Akt signaling, with the receptor complex physically associating with Nox1 to generate ROS that amplify these cascades [PMID:11123287, PMID:23541442]. T cell-intrinsic IL-18R/MyD88 signaling is essential for Th1 proliferation, CD4 cytotoxic T cell differentiation, and γδ T cell effector function during intracellular pathogen infection, and also constrains ILC expansion by inhibiting proliferation and inducing apoptosis [PMID:28895840, PMID:35670567, PMID:32450614, PMID:35874724]. IL18R1 transcription is repressed by GATA-3 and Stat6 during Th2 differentiation, and its downregulation via TGF-β/IFN-αβ-dependent suppression of Tcf-1 marks kidney tissue-resident CD8+ T cells [PMID:18714006, PMID:33474536].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Before its ligand was known, the identification of IL18R1 as a novel IL-1R family member whose cytoplasmic domain could activate NF-κB established that this orphan receptor possessed intrinsic signaling competence through the TIR domain.\",\n      \"evidence\": \"Chimeric receptor (IL-1R ectodomain/IL18R1 cytoplasmic domain) transfected into COS cells with NF-κB and IL-8 promoter reporter assays\",\n      \"pmids\": [\"8626725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cognate ligand not yet identified\", \"Accessory chain requirement unknown\", \"Downstream adaptor molecules not defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The requirement for a heterodimeric receptor was resolved when reconstitution showed that IL-18Rα alone binds IL-18 but cannot signal, and co-expression of IL-18Rβ restores IL-18-dependent NF-κB activation and cytokine induction.\",\n      \"evidence\": \"COS-1 transfection of IL-18Rβ cDNA, luciferase reporter, IL-8 ELISA, anti-IL-18Rα blocking antibody\",\n      \"pmids\": [\"11123287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of α/β heterodimerization not determined\", \"Stoichiometry of receptor complex not addressed\", \"Identity of a second IL-18R ligand (IL-1H) only preliminarily characterized\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"IL-18Rα expression was shown to be dynamically regulated during Th1/Th2 differentiation: IL-12 upregulates both receptor chains, while IL-4 suppresses IL-18Rα unless IFN-γ counteracts, establishing IL-18Rα surface levels as a checkpoint in T helper lineage commitment.\",\n      \"evidence\": \"T cell differentiation using IFN-γ−/− mice, IL-4 neutralization, flow cytometry for surface IL-18Rα\",\n      \"pmids\": [\"12055229\", \"11123287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cis-regulatory elements governing IL-18Rα transcription not mapped\", \"Direct versus indirect effects of IFN-γ on IL-18Rα promoter not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Beyond immune signaling, IL-18R was found to mediate direct cell motility: IL-18 induces actin polymerization and chemotaxis in dendritic cells, and NF-κB-dependent IL-18Rβ upregulation in cardiomyocytes established the receptor's role outside classical lymphoid compartments.\",\n      \"evidence\": \"Boyden chamber migration assay and F-actin staining on monocyte-derived DCs; NF-κB inhibitor (PDTC) treatment in primary cardiomyocytes\",\n      \"pmids\": [\"14662834\", \"12684057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling intermediates linking IL-18R to actin remodeling not identified\", \"In vivo relevance of DC migration via IL-18R not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The transcriptional basis of IL-18Rα silencing in Th2 cells was defined: GATA-3 directly binds the Il18r1 locus at conserved non-coding regions and represses transcription, and this repression requires Stat6, linking IL-4/Stat6/GATA-3 to chromatin-level control of IL-18 responsiveness.\",\n      \"evidence\": \"ChIP for GATA-3, DNase hypersensitivity assay, ectopic GATA-3 in Th1 cells, Stat6−/− mice\",\n      \"pmids\": [\"18714006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise enhancer-promoter architecture of the Il18r1 locus not resolved\", \"Whether GATA-3-mediated repression is reversible in committed Th2 cells not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The discovery that IL-18Rα/β physically associates with Nox1 and that IL-18 enhances this interaction revealed a proximal ROS-generating mechanism upstream of NF-κB/JNK and TRAF3IP2, explaining how IL-18R drives smooth muscle cell migration.\",\n      \"evidence\": \"Co-immunoprecipitation and GST pull-down for IL-18R/Nox1 association; Nox1 ROS assay, NF-κB/AP-1 reporters, and migration assay in human coronary artery SMCs\",\n      \"pmids\": [\"23541442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface between IL-18R and Nox1 not mapped\", \"Whether IL-18R/Nox1 complex forms in other cell types not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Using mixed bone marrow chimeras and adoptive transfer rescue, IL-18R/MyD88 was established as a T cell-intrinsic signaling axis essential for Th1 proliferation, survival, and host protection against intracellular pathogens (T. cruzi, Salmonella, Chlamydia, Brucella).\",\n      \"evidence\": \"Il18r1−/− and Myd88−/− mixed chimeras, transcriptomics, adoptive transfer of WT CD4+ T cells, multiple intracellular pathogen infection models\",\n      \"pmids\": [\"28895840\", \"28817719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific MyD88-dependent transcriptional targets downstream of IL-18R in T cells not fully cataloged\", \"Whether IL-18R signals through IRAK kinases in T cells not directly shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"IL-18R/MyD88 signaling was shown to be intrinsically required not only in CD4+ T cells but also in γδ T cells for their proliferation and cytotoxic effector function during T. cruzi infection, broadening the receptor's role to unconventional T cell subsets.\",\n      \"evidence\": \"Il18r1−/− mice, adoptive transfer of WT γδ T cells rescuing susceptibility, intracellular cytokine staining\",\n      \"pmids\": [\"32450614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of IL-18R regulation of granzyme B expression in γδ T cells not defined\", \"Whether IL-18R signaling differs mechanistically in γδ versus αβ T cells not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Two new biological contexts for IL-18R were established: cell-intrinsic IL-18R signaling drives hematopoietic stem cell quiescence during severe infection, and downregulation of IL-18R via TGF-β/IFN-αβ/Tcf-1 suppression marks kidney tissue-resident CD8+ T cells.\",\n      \"evidence\": \"Il18r1−/− mice in Ehrlichia infection for HSC quiescence; parabiosis, scRNA-seq, and cytokine pathway dissection for kidney Trm\",\n      \"pmids\": [\"34798063\", \"33474536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which IL-18R enforces HSC quiescence (cell cycle arrest pathway) not identified\", \"Whether IL-18R downregulation is a universal Trm marker across tissues not determined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"IL-18R/MyD88 was identified as the critical T cell-intrinsic pathway for CD4 cytotoxic T lymphocyte (CD4CTL) differentiation, with Il18r1−/− and Myd88−/− CD4+ T cells phenocopying each other in mixed chimeras, and IL-18R signaling was separately shown to constrain ILC expansion by inhibiting proliferation and inducing apoptosis.\",\n      \"evidence\": \"Mixed bone marrow chimeras, adoptive transfer of GzB+ CD4+ T cells, single-cell transcriptomics for CD4CTL; Il18r1−/− and Il18−/− mice with in vitro ILC differentiation and adoptive transfer for ILC function\",\n      \"pmids\": [\"35670567\", \"35874724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Epigenetic programs downstream of IL-18R that commit CD4 cells to cytotoxic fate not mapped\", \"Whether IL-18R-mediated ILC apoptosis is caspase-dependent not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of IL-18Rα/IL-18Rβ heterodimerization, the full spectrum of adaptor complexes recruited to the IL-18R TIR domain in different cell types, and whether IL-18R signals through distinct downstream pathways in hematopoietic stem cells versus lymphocytes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of the IL-18/IL-18Rα/IL-18Rβ signaling complex\", \"IRAK recruitment to IL-18R TIR domain not directly demonstrated\", \"Cell-type-specific signaling outputs downstream of IL-18R not systematically compared\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12, 13, 14, 17, 19, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 10, 11, 18]}\n    ],\n    \"complexes\": [\n      \"IL-18Rα/IL-18Rβ heterodimer\",\n      \"IL-18R/Nox1 complex\"\n    ],\n    \"partners\": [\n      \"IL18RAP\",\n      \"NOX1\",\n      \"MYD88\",\n      \"GATA3\",\n      \"TRAF3IP2\",\n      \"IL18\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}