{"gene":"IL1B","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1995,"finding":"Cell-type-specific expression of the IL1B gene in monocytes/macrophages is dependent on binding of the hematopoietic transcription factor Spi-1/PU.1 to two sites in the IL1B promoter (between -50 and -39, and between -115 and -97). Mutation of the proximal site abrogated binding and reduced promoter activity; a dominant-negative Spi-1 inhibited reporter expression in monocytes; and cotransfection of Spi-1 into Spi-1-deficient HeLa cells activated the IL1B promoter.","method":"Promoter-reporter assays, EMSA, dominant-negative expression vector, cotransfection in HeLa cells, site-directed mutagenesis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (EMSA, mutagenesis, dominant-negative, heterologous cell rescue) in a single rigorous study","pmids":["7799967"],"is_preprint":false},{"year":1991,"finding":"IL-1β protein is absent from unstimulated human monocytes (no pre-formed mRNA or intracellular protein). After LPS or monosodium urate crystal stimulation, IL1B mRNA accumulates rapidly, followed by intracellular IL-1β protein that is subsequently released (approximately 60% secreted by 9 h). Other crystal types (hydroxylapatite, calcium pyrophosphate dihydrate) failed to induce significant IL-1β production.","method":"Time-course measurement of IL-1β mRNA and protein in human adherent monocytes after LPS or crystal stimulation; intracellular and secreted protein quantification","journal":"Immunology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct kinetic measurement of mRNA and protein in primary human cells, single lab, two orthogonal readouts","pmids":["1663080"],"is_preprint":false},{"year":2018,"finding":"In CD4 T cells, IL1B gene transcription is activated by CD3/CD28 stimulation independently of Spi-1/PU.1 (which is absent from the IL1B promoter in T cells). Unlike monocytes, activated CD4 T cells display bivalent H3K4me3+/H3K27me3+ nucleosome marks at the IL1B promoter, reflecting low transcriptional activity. Some CD4 T cell subsets accumulate higher cytoplasmic proIL-1β protein than unstimulated monocytes despite relatively low mRNA levels.","method":"ChIP for H3K4me3/H3K27me3 at the IL1B locus, RT-PCR for IL1B mRNA, immunoblot for proIL-1β protein, ex vivo CD3/CD28 activation of primary human CD4 T cells","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and mRNA/protein measurements in primary human cells, single lab, two orthogonal methods","pmids":["30300855"],"is_preprint":false},{"year":2020,"finding":"IL-1β increases intestinal tight junction (TJ) permeability by upregulating MIR200C-3p, which degrades occludin mRNA. IL-1β treatment of Caco-2 cells rapidly elevated MIR200C-3p and reduced occludin mRNA and protein without affecting other transmembrane TJ proteins. AntagomiR-200C prevented these effects and protected against IL-1β-induced permeability increases in vivo. 3D molecular modeling and mutational analyses identified the nucleotide bases in occludin mRNA 3'UTR that interact with MIR200C-3p.","method":"Caco-2 monolayer permeability assay, immunoblot, RT-PCR, antagomiR transfection, in vivo mouse intestinal perfusion, laser capture microdissection of enterocytes, 3D molecular modeling and mutational analysis of miRNA–mRNA interaction","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (cell culture, in vivo, structural modeling, mutagenesis) replicated in mouse and patient tissue","pmids":["32569770"],"is_preprint":false},{"year":2017,"finding":"PTPN22 regulates NLRP3-mediated IL-1β secretion via an autophagy-dependent mechanism: loss of PTPN22 increases NLRP3 phosphorylation, phosphorylated NLRP3 is sequestered into autophagosomes and degraded, thereby inhibiting NLRP3 inflammasome activation and IL-1β secretion. Loss of autophagy abrogates the inhibitory effect on NLRP3 activation seen upon PTPN22 loss.","method":"Autophagosome fractionation, immunofluorescence co-localization with LC3B and LAMP2, siRNA knockdown of ATG7/SQSTM1, pharmacological autophagy inhibition, point mutation (Lys316Arg) of NLRP3","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple approaches (genetic KD, pharmacological inhibition, mutagenesis, imaging), single lab","pmids":["28786745"],"is_preprint":false},{"year":2014,"finding":"Autophagy-dependent degradation of PELI3 (an E3 ubiquitin ligase and TLR4-signaling scaffold) attenuates IL1B mRNA expression in macrophages. PELI3 knockdown reduced LPS-induced IL1b expression. SQSTM1/p62 binds PELI3; inhibition of autophagy (via wortmannin, bafilomycin A1, or siRNA against SQSTM1/ATG7) increased PELI3 protein. PELI3 is ubiquitinated after LPS stimulation; mutation of Lys316 to Arg attenuated autophagy-dependent PELI3 degradation. PELI3 co-localized with LC3B and LAMP2 in autophagosomes.","method":"siRNA knockdown, pharmacological autophagy inhibition, Co-IP, immunofluorescence, point mutagenesis (Lys316Arg), RT-PCR for Il1b","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in a single lab; direct mechanistic link between PELI3 autophagy and IL1B expression","pmids":["25483963"],"is_preprint":false},{"year":2019,"finding":"LIPUS (low-intensity pulsed ultrasound) inhibits mature IL-1β production in LPS/ATP-stimulated macrophages via SQSTM1-dependent autophagic degradation of PKM2. LIPUS upregulated autophagy flux and promoted SQSTM1–PKM2 complex formation; SQSTM1 knockdown reversed LIPUS-induced PKM2 degradation and restored mature IL-1β production.","method":"Co-IP (SQSTM1-PKM2), siRNA knockdown of SQSTM1, ELISA for mature IL-1β, autophagy inhibition assays, in vivo DMM mouse model","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus knockdown rescue, single lab, in vitro and in vivo","pmids":["31500508"],"is_preprint":false},{"year":2018,"finding":"IL-1β-induced inflammatory gene responses in primary epidermal keratinocytes are entirely dependent on the MyD88 adaptor protein. CRISPR/Cas9 inactivation of MyD88 completely abolished IL-1β (and IL-36G) expression responses of a 225-gene shared cytokine-response signature including upregulation of IL1A, IL1B, IL36G, and inhibitors such as IL1RN.","method":"RNA-seq of primary human keratinocytes, CRISPR/Cas9 knockout of MYD88, cytokine stimulation (IL-1B, IL-36A/B/G)","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with genome-wide transcriptomic readout, single lab","pmids":["29434599"],"is_preprint":false},{"year":2010,"finding":"In the mouse uterus during early pregnancy, macrophage-derived IL1B (together with LIF) regulates epithelial cell Fut2 mRNA expression and terminal fucosylation of embryo attachment ligands. Neutralizing antibodies to IL1B inhibited macrophage-conditioned medium-stimulated Fut2 upregulation in uterine epithelial cells in vitro; macrophage depletion in vivo reduced UEA-1 and LewisX staining on luminal epithelium.","method":"Epithelial cell co-culture with macrophages or conditioned medium, neutralizing antibody blockade of IL1B/LIF, in vivo macrophage depletion (Cd11b-dtr transgenic mice), laser capture microdissection, quantitative RT-PCR, lectin/immunostaining","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro neutralization and in vivo depletion with functional readout, single lab","pmids":["20864644"],"is_preprint":false},{"year":2012,"finding":"In porcine uterine endometrium during peri-implantation, IL1B upregulates expression of its own receptor subunits (IL1R1 in a dose-dependent manner, IL1RAP in response to IL1B and estradiol cooperatively) and stimulates expression of prostaglandin-synthetic rate-limiting enzymes PTGS1 and PTGS2.","method":"In vitro treatment of porcine uterine endometrial cells with recombinant IL1B, dose-response RT-PCR for IL1R1, IL1RAP, PTGS1, PTGS2","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct in vitro treatment with functional gene-expression readout, single lab, multiple targets measured","pmids":["22572995"],"is_preprint":false},{"year":2012,"finding":"IL-1β produced by metastatic ovarian cancer cells induces mesothelial cell β1-integrin expression, facilitating tumor cell adhesion to the peritoneum. Neutralizing antibodies to IL-1β inhibited adhesion of metastatic MFOC3 cells to mesothelial monolayers; recombinant IL-1β enhanced adhesion; anti-β1-integrin antibody inhibited adhesion in vitro and reduced metastases in vivo.","method":"Co-culture adhesion assay on mesothelial monolayers, neutralizing antibody blockade, recombinant IL-1β stimulation, anti-β1-integrin blocking antibody, in vivo SCID mouse metastasis model","journal":"Journal of ovarian research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal neutralization plus in vivo confirmation, single lab","pmids":["22296757"],"is_preprint":false},{"year":2008,"finding":"IL1B promoter haplotypes (defined by SNPs at -511, -1464, -3737) predict in vivo IL-1β protein levels in gingival tissue fluid and serum CRP, and validated in stimulated PBMCs: haplotype-pairs associated with higher in vivo IL-1β caused 86–287% more IL-1β production in vitro, demonstrating that individual SNP function is governed by haplotype context affecting IL1B transcription.","method":"Haplotype analysis of 900 gingival fluid samples (IL-1β protein by immunoassay), serum CRP, validation in stimulated PBMCs (N=70)","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in vivo haplotype-protein correlation validated in independent PBMC stimulation experiment","pmids":["18369665"],"is_preprint":false},{"year":2013,"finding":"Low picogram/mL circulating levels of IL-1β combined with IL-6 directly trigger pancreatic islet dysfunction by reducing ER calcium storage, activating ER stress responses (Nos2, Bip, Atf4, Ddit3/CHOP), impairing glucose-stimulated insulin secretion, and increasing cell death—effects that were more severe in islets from prediabetic db/db mice. Subcutaneous osmotic mini-pump delivery of IL-1β+IL-6 in mice reproduced islet calcium handling and secretion defects observed in vitro.","method":"In vitro cytokine treatment of isolated mouse and human islets, intracellular calcium imaging, ER calcium measurements, ER stress gene expression, GSIS assay, in vivo osmotic mini-pump cytokine delivery","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo orthogonal approaches in a single lab with multiple mechanistic readouts","pmids":["23836031"],"is_preprint":false},{"year":2020,"finding":"IL1B triggers SASP production (IL8, IL6, TNFA, CCL2) and upregulates cell adhesion molecule expression in bovine oviduct epithelial cells (OECs). CCL2 induced by IL1B is essential for neutrophil (PMN) migration toward OEC-conditioned medium; CCL2 inhibition, but not IL8/CXCR2 blockade, significantly reduced immune cell migration. IL1B also increased PMN adhesion to OECs, leading to further SASP amplification via direct PMN–OEC interaction.","method":"In vitro cytokine treatment of bovine OECs, PMN migration assay with conditioned medium, CCL2/CXCR2 inhibitor blockade, flow cytometry for PMN adhesion","journal":"American journal of reproductive immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological receptor blockade identifying CCL2 as the key mediator, single lab, multiple assays","pmids":["33099841"],"is_preprint":false},{"year":2024,"finding":"lnc-HZ06 promotes STAT4-mediated IL1B mRNA transcription and enhances IL1B mRNA stability by promoting formation of a METTL3/HuR/IL1B mRNA ternary complex, upregulating IL-1β levels in BaP/BPDE-exposed trophoblast cells. Knockdown of murine lnc-hz06 (which downregulates Il1b levels) or Il1b directly alleviated miscarriage in BaP-exposed mice. BPDE exposure promotes TBP-mediated lnc-HZ06 transcription upstream of this pathway.","method":"siRNA/shRNA knockdown, RIP (RNA immunoprecipitation for METTL3/HuR/IL1B mRNA complex), ChIP for STAT4 at IL1B promoter, in vivo BaP-exposed mouse miscarriage model","journal":"Journal of hazardous materials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic steps validated by RIP, ChIP, and in vivo knockdown rescue; single lab","pmids":["38991640"],"is_preprint":false}],"current_model":"IL-1β (IL1B) is a pro-inflammatory cytokine whose expression in monocytes/macrophages depends on Spi-1/PU.1 binding to the IL1B promoter, while in CD4 T cells transcription proceeds from a bivalent promoter independently of Spi-1; mature IL-1β secretion requires NLRP3 inflammasome-mediated processing (regulated by autophagy via PELI3 and PKM2 degradation, and by PTPN22-driven NLRP3 phosphorylation), and downstream signaling through MyD88 mediates its transcriptional responses in target cells such as keratinocytes; IL-1β acts extracellularly to increase intestinal tight junction permeability via MIR200C-3p-dependent occludin mRNA degradation, to induce mesothelial β1-integrin expression facilitating tumor cell adhesion, to regulate uterine Fut2 and prostaglandin synthesis during implantation, and to drive ER stress-mediated pancreatic islet dysfunction and CCL2-dependent neutrophil recruitment in reproductive epithelium."},"narrative":{"mechanistic_narrative":"IL1B encodes a pro-inflammatory cytokine whose production is gated at the levels of transcription, post-transcriptional control, and inflammasome-dependent processing, and which then acts extracellularly to remodel epithelial and stromal tissue [PMID:7799967, PMID:1663080, PMID:28786745]. In monocytes/macrophages IL1B is not pre-formed but is induced rapidly upon LPS or monosodium urate crystal stimulation, with transcription depending on binding of the hematopoietic transcription factor Spi-1/PU.1 to two sites in the IL1B promoter [PMID:7799967, PMID:1663080]. In CD4 T cells transcription instead proceeds from a bivalent H3K4me3/H3K27me3 promoter independently of Spi-1, yielding cytoplasmic proIL-1β despite low mRNA [PMID:30300855], while promoter haplotype context quantitatively sets the level of IL-1β produced [PMID:18369665]. Beyond transcription, IL1B output is constrained by autophagy: autophagic degradation of the TLR4 scaffold PELI3 limits IL1B mRNA expression [PMID:25483963], degradation of PKM2 limits mature IL-1β production [PMID:31500508], and PTPN22-driven NLRP3 phosphorylation targets NLRP3 to autophagosomes to suppress inflammasome-mediated secretion [PMID:28786745]. Secreted IL-1β signals through the MyD88 adaptor to drive inflammatory gene programs, as MyD88 inactivation abolishes the IL-1β transcriptional response in keratinocytes [PMID:29434599]. Functionally, IL-1β increases intestinal tight-junction permeability by inducing MIR200C-3p, which degrades occludin mRNA [PMID:32569770], induces mesothelial β1-integrin to facilitate tumor cell adhesion [PMID:22296757], triggers ER stress and insulin-secretion defects in pancreatic islets [PMID:23836031], and drives CCL2-dependent neutrophil recruitment and adhesion-molecule expression in reproductive epithelium [PMID:33099841]. In reproductive tissue it also regulates uterine Fut2 expression and fucosylation of embryo-attachment ligands and stimulates prostaglandin-synthetic enzymes PTGS1/PTGS2 and its own receptor subunits [PMID:20864644, PMID:22572995].","teleology":[{"year":1991,"claim":"Established that IL-1β is an inducible rather than constitutive product, defining the kinetics by which stimulated monocytes accumulate IL1B mRNA, protein, and then secrete it.","evidence":"Time-course of IL-1β mRNA and protein in human adherent monocytes after LPS or crystal stimulation","pmids":["1663080"],"confidence":"Medium","gaps":["Does not resolve the transcription factors driving induction","Does not define the processing/secretion machinery"]},{"year":1995,"claim":"Identified the cell-type-specific transcriptional basis for monocyte IL1B expression by showing Spi-1/PU.1 binds and activates the IL1B promoter.","evidence":"Promoter-reporter assays, EMSA, dominant-negative Spi-1, and cotransfection rescue in HeLa cells with site-directed mutagenesis","pmids":["7799967"],"confidence":"High","gaps":["Does not address regulation in non-myeloid lineages","Does not connect promoter occupancy to signal-induced kinetics"]},{"year":2008,"claim":"Showed that IL1B promoter haplotype context, not single SNPs alone, quantitatively governs in vivo and ex vivo IL-1β production levels.","evidence":"Haplotype analysis of gingival fluid IL-1β, serum CRP, and stimulated PBMC validation","pmids":["18369665"],"confidence":"Medium","gaps":["Correlative for individual SNP mechanism","Does not identify the transcription factors whose binding the haplotypes alter"]},{"year":2018,"claim":"Revealed lineage-divergent IL1B regulation by demonstrating Spi-1-independent, bivalent-chromatin-poised transcription in CD4 T cells distinct from monocytes.","evidence":"ChIP for H3K4me3/H3K27me3, RT-PCR, and immunoblot of proIL-1β in CD3/CD28-activated primary human CD4 T cells","pmids":["30300855"],"confidence":"Medium","gaps":["Does not identify the T-cell-specific activating transcription factors","Does not establish whether T-cell proIL-1β is processed and secreted"]},{"year":2014,"claim":"Defined autophagy as a brake on IL1B mRNA expression by showing SQSTM1-mediated autophagic degradation of the TLR4 scaffold PELI3.","evidence":"siRNA knockdown, autophagy inhibition, Co-IP, Lys316Arg mutagenesis, and RT-PCR in macrophages","pmids":["25483963"],"confidence":"Medium","gaps":["Single lab","Does not quantify contribution relative to other PELI3-independent pathways"]},{"year":2017,"claim":"Linked PTPN22 to inflammasome control by showing PTPN22 loss increases NLRP3 phosphorylation, routing NLRP3 to autophagic degradation and suppressing IL-1β secretion.","evidence":"Autophagosome fractionation, LC3B/LAMP2 co-localization, ATG7/SQSTM1 knockdown, autophagy inhibition, and NLRP3 K316R mutation","pmids":["28786745"],"confidence":"Medium","gaps":["Single lab","Kinase responsible for NLRP3 phosphorylation downstream of PTPN22 not defined"]},{"year":2019,"claim":"Extended autophagic control to mature cytokine output by showing SQSTM1-dependent degradation of PKM2 suppresses mature IL-1β production.","evidence":"SQSTM1-PKM2 Co-IP, siRNA knockdown rescue, ELISA, and an in vivo DMM mouse model under LIPUS","pmids":["31500508"],"confidence":"Medium","gaps":["Single lab","Mechanism connecting PKM2 levels to inflammasome processing not fully resolved"]},{"year":2018,"claim":"Established MyD88 as the obligate adaptor for IL-1β signal transduction in target epithelium.","evidence":"RNA-seq with CRISPR/Cas9 MYD88 knockout in primary human keratinocytes under IL-1β stimulation","pmids":["29434599"],"confidence":"Medium","gaps":["Restricted to keratinocytes","Does not dissect downstream NF-κB versus other branches"]},{"year":2010,"claim":"Demonstrated a tissue-remodeling role for IL-1β in reproduction by showing macrophage-derived IL1B regulates uterine epithelial Fut2 and fucosylation of attachment ligands.","evidence":"Epithelial-macrophage co-culture, IL1B neutralization, in vivo Cd11b-dtr macrophage depletion, LCM, and lectin staining in mouse uterus","pmids":["20864644"],"confidence":"Medium","gaps":["Does not establish the receptor/signaling route in epithelium","Co-dependency with LIF not fully separated"]},{"year":2012,"claim":"Showed IL-1β amplifies its own signaling and prostaglandin synthesis in peri-implantation endometrium, and separately that tumor-derived IL-1β promotes peritoneal metastatic adhesion via mesothelial β1-integrin.","evidence":"Recombinant IL1B dose-response RT-PCR in porcine endometrium; co-culture adhesion assays, IL-1β and β1-integrin neutralization, and SCID mouse metastasis model","pmids":["22572995","22296757"],"confidence":"Medium","gaps":["Endometrial work is porcine and gene-expression-level only","Adhesion mechanism does not define the IL-1β receptor signaling step in mesothelium"]},{"year":2013,"claim":"Demonstrated that low circulating IL-1β, acting with IL-6, drives ER-stress-mediated pancreatic islet dysfunction and impaired insulin secretion.","evidence":"Cytokine treatment of mouse/human islets with calcium imaging, ER stress gene profiling, GSIS, and in vivo osmotic mini-pump delivery","pmids":["23836031"],"confidence":"Medium","gaps":["Cannot isolate IL-1β from IL-6 contribution","Receptor and signaling intermediates in β-cells not mapped"]},{"year":2020,"claim":"Defined two distinct effector mechanisms: IL-1β disrupts intestinal barrier integrity via MIR200C-3p-mediated occludin mRNA degradation, and recruits neutrophils via CCL2 in reproductive epithelium.","evidence":"Caco-2 permeability with antagomiR and in vivo perfusion plus miRNA-mRNA structural modeling; bovine OEC PMN-migration assays with CCL2/CXCR2 blockade","pmids":["32569770","33099841"],"confidence":"High","gaps":["Does not link these effector outputs back to IL-1β receptor/MyD88 signaling explicitly","CCL2 work is bovine"]},{"year":2024,"claim":"Identified a post-transcriptional amplifier of IL1B in trophoblasts whereby lnc-HZ06 promotes STAT4-driven transcription and METTL3/HuR-mediated mRNA stabilization, linking IL-1β dysregulation to miscarriage.","evidence":"RIP for the METTL3/HuR/IL1B complex, ChIP for STAT4, and in vivo lnc-hz06/Il1b knockdown rescue in BaP-exposed mice","pmids":["38991640"],"confidence":"Medium","gaps":["Single lab","Generality of lnc-HZ06 control beyond toxicant-exposed trophoblasts unknown"]},{"year":null,"claim":"How the divergent transcriptional inputs, autophagy-based brakes, and inflammasome processing are integrated in a single cell to set the quantitative threshold and timing of mature IL-1β release remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified quantitative model of transcription-to-secretion flux","Receptor-proximal signaling for most effector phenotypes not mapped within the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[7,10,12,3,13]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[9,8]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,4,7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,14]}],"complexes":[],"partners":["MYD88","IL1R1","IL1RAP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P01584","full_name":"Interleukin-1 beta","aliases":["Catabolin"],"length_aa":269,"mass_kda":30.7,"function":"Potent pro-inflammatory cytokine (PubMed:10653850, PubMed:12794819, PubMed:28331908, PubMed:3920526). Initially discovered as the major endogenous pyrogen, induces prostaglandin synthesis, neutrophil influx and activation, T-cell activation and cytokine production, B-cell activation and antibody production, and fibroblast proliferation and collagen production (PubMed:3920526). Promotes Th17 differentiation of T-cells. Synergizes with IL12/interleukin-12 to induce IFNG synthesis from T-helper 1 (Th1) cells (PubMed:10653850). Plays a role in angiogenesis by inducing VEGF production synergistically with TNF and IL6 (PubMed:12794819). Involved in transduction of inflammation downstream of pyroptosis: its mature form is specifically released in the extracellular milieu by passing through the gasdermin-D (GSDMD) pore (PubMed:33377178, PubMed:33883744). Acts as a sensor of S.pyogenes infection in skin: cleaved and activated by pyogenes SpeB protease, leading to an inflammatory response that prevents bacterial growth during invasive skin infection (PubMed:28331908)","subcellular_location":"Cytoplasm, cytosol; Secreted; Lysosome; Secreted, extracellular exosome","url":"https://www.uniprot.org/uniprotkb/P01584/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL1B","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL1B","total_profiled":1310},"omim":[{"mim_id":"621395","title":"DEAD-BOX HELICASE 19A; DDX19A","url":"https://www.omim.org/entry/621395"},{"mim_id":"621254","title":"IMMUNODEFICIENCY 133 WITH ECTODERMAL DYSPLASIA WITH OR WITHOUT PERIPHERAL NEUROPATHY; IMD133","url":"https://www.omim.org/entry/621254"},{"mim_id":"621233","title":"IMMUNODYSREGULATION WITH VARIABLE IMMUNODEFICIENCY AND AUTOIMMUNITY; IMDIA","url":"https://www.omim.org/entry/621233"},{"mim_id":"621228","title":"LONG INTERGENIC NONCODING RNA 1013; LINC01013","url":"https://www.omim.org/entry/621228"},{"mim_id":"621030","title":"AUTOINFLAMMATION, PANNICULITIS, AND DERMATOSIS SYNDROME, AUTOSOMAL DOMINANT; AIPDSA","url":"https://www.omim.org/entry/621030"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":190.0},{"tissue":"urinary bladder","ntpm":117.2}],"url":"https://www.proteinatlas.org/search/IL1B"},"hgnc":{"alias_symbol":["IL1F2","IL-1B","IL1-BETA"],"prev_symbol":[]},"alphafold":{"accession":"P01584","domains":[{"cath_id":"2.80.10.50","chopping":"122-267","consensus_level":"high","plddt":95.2104,"start":122,"end":267}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P01584","model_url":"https://alphafold.ebi.ac.uk/files/AF-P01584-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P01584-F1-predicted_aligned_error_v6.png","plddt_mean":76.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL1B","jax_strain_url":"https://www.jax.org/strain/search?query=IL1B"},"sequence":{"accession":"P01584","fasta_url":"https://rest.uniprot.org/uniprotkb/P01584.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P01584/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P01584"}},"corpus_meta":[{"pmid":"32569770","id":"PMC_32569770","title":"IL1B Increases Intestinal Tight Junction Permeability by Up-regulation of MIR200C-3p, Which Degrades Occludin mRNA.","date":"2020","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/32569770","citation_count":197,"is_preprint":false},{"pmid":"26476141","id":"PMC_26476141","title":"Prebiotic administration normalizes lipopolysaccharide (LPS)-induced anxiety and cortical 5-HT2A receptor and IL1-β levels in male mice.","date":"2016","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/26476141","citation_count":163,"is_preprint":false},{"pmid":"29760166","id":"PMC_29760166","title":"The role of IL-1B in breast cancer bone metastasis.","date":"2018","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29760166","citation_count":148,"is_preprint":false},{"pmid":"34279540","id":"PMC_34279540","title":"Single-cell analysis of human skin identifies CD14+ type 3 dendritic cells co-producing IL1B and IL23A in psoriasis.","date":"2021","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34279540","citation_count":137,"is_preprint":false},{"pmid":"10380697","id":"PMC_10380697","title":"IL1B gene polymorphisms influence the course and severity of inflammatory bowel disease.","date":"1999","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/10380697","citation_count":124,"is_preprint":false},{"pmid":"7799967","id":"PMC_7799967","title":"Monocyte expression of the human prointerleukin 1 beta gene (IL1B) is dependent on promoter sequences which bind the hematopoietic transcription factor Spi-1/PU.1.","date":"1995","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7799967","citation_count":122,"is_preprint":false},{"pmid":"23836031","id":"PMC_23836031","title":"Circulating levels of IL-1B+IL-6 cause ER stress and dysfunction in islets from prediabetic male 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materials","url":"https://pubmed.ncbi.nlm.nih.gov/38991640","citation_count":16,"is_preprint":false},{"pmid":"28914761","id":"PMC_28914761","title":"Flavonolignans Inhibit IL1-β-Induced Cross-Talk between Blood Platelets and Leukocytes.","date":"2017","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/28914761","citation_count":16,"is_preprint":false},{"pmid":"32391643","id":"PMC_32391643","title":"Evaluation of genetic variants in IL-1B and its interaction with the predisposition of osteoporosis in the northwestern Chinese Han population.","date":"2020","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32391643","citation_count":16,"is_preprint":false},{"pmid":"23784458","id":"PMC_23784458","title":"Current evidences on IL1B polymorphisms and lung cancer susceptibility: a meta-analysis.","date":"2013","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23784458","citation_count":15,"is_preprint":false},{"pmid":"35280410","id":"PMC_35280410","title":"IL-1B can serve as a healing process and is a critical regulator of diabetic foot ulcer.","date":"2022","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35280410","citation_count":14,"is_preprint":false},{"pmid":"28646347","id":"PMC_28646347","title":"Alendronate treatment induces IL-1B expression and apoptosis in glioblastoma cell line.","date":"2017","source":"Inflammopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28646347","citation_count":14,"is_preprint":false},{"pmid":"37147350","id":"PMC_37147350","title":"Common variants of pro-inflammatory gene IL1B and interactions with PPP1R13L and POLR1G in relation to lung cancer among Northeast Chinese.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37147350","citation_count":14,"is_preprint":false},{"pmid":"24654313","id":"PMC_24654313","title":"Polymorphisms of the IL12B, IL1B, and TNFA genes and susceptibility to asthma.","date":"2013","source":"Journal of investigational allergology & clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24654313","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":59221,"output_tokens":4618,"usd":0.123467,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12784,"output_tokens":4440,"usd":0.08746,"stage2_stop_reason":"end_turn"},"total_usd":0.210927,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Cell-type-specific expression of the IL1B gene in monocytes/macrophages is dependent on binding of the hematopoietic transcription factor Spi-1/PU.1 to two sites in the IL1B promoter (between -50 and -39, and between -115 and -97). Mutation of the proximal site abrogated binding and reduced promoter activity; a dominant-negative Spi-1 inhibited reporter expression in monocytes; and cotransfection of Spi-1 into Spi-1-deficient HeLa cells activated the IL1B promoter.\",\n      \"method\": \"Promoter-reporter assays, EMSA, dominant-negative expression vector, cotransfection in HeLa cells, site-directed mutagenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (EMSA, mutagenesis, dominant-negative, heterologous cell rescue) in a single rigorous study\",\n      \"pmids\": [\"7799967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"IL-1β protein is absent from unstimulated human monocytes (no pre-formed mRNA or intracellular protein). After LPS or monosodium urate crystal stimulation, IL1B mRNA accumulates rapidly, followed by intracellular IL-1β protein that is subsequently released (approximately 60% secreted by 9 h). Other crystal types (hydroxylapatite, calcium pyrophosphate dihydrate) failed to induce significant IL-1β production.\",\n      \"method\": \"Time-course measurement of IL-1β mRNA and protein in human adherent monocytes after LPS or crystal stimulation; intracellular and secreted protein quantification\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct kinetic measurement of mRNA and protein in primary human cells, single lab, two orthogonal readouts\",\n      \"pmids\": [\"1663080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In CD4 T cells, IL1B gene transcription is activated by CD3/CD28 stimulation independently of Spi-1/PU.1 (which is absent from the IL1B promoter in T cells). Unlike monocytes, activated CD4 T cells display bivalent H3K4me3+/H3K27me3+ nucleosome marks at the IL1B promoter, reflecting low transcriptional activity. Some CD4 T cell subsets accumulate higher cytoplasmic proIL-1β protein than unstimulated monocytes despite relatively low mRNA levels.\",\n      \"method\": \"ChIP for H3K4me3/H3K27me3 at the IL1B locus, RT-PCR for IL1B mRNA, immunoblot for proIL-1β protein, ex vivo CD3/CD28 activation of primary human CD4 T cells\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and mRNA/protein measurements in primary human cells, single lab, two orthogonal methods\",\n      \"pmids\": [\"30300855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-1β increases intestinal tight junction (TJ) permeability by upregulating MIR200C-3p, which degrades occludin mRNA. IL-1β treatment of Caco-2 cells rapidly elevated MIR200C-3p and reduced occludin mRNA and protein without affecting other transmembrane TJ proteins. AntagomiR-200C prevented these effects and protected against IL-1β-induced permeability increases in vivo. 3D molecular modeling and mutational analyses identified the nucleotide bases in occludin mRNA 3'UTR that interact with MIR200C-3p.\",\n      \"method\": \"Caco-2 monolayer permeability assay, immunoblot, RT-PCR, antagomiR transfection, in vivo mouse intestinal perfusion, laser capture microdissection of enterocytes, 3D molecular modeling and mutational analysis of miRNA–mRNA interaction\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (cell culture, in vivo, structural modeling, mutagenesis) replicated in mouse and patient tissue\",\n      \"pmids\": [\"32569770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PTPN22 regulates NLRP3-mediated IL-1β secretion via an autophagy-dependent mechanism: loss of PTPN22 increases NLRP3 phosphorylation, phosphorylated NLRP3 is sequestered into autophagosomes and degraded, thereby inhibiting NLRP3 inflammasome activation and IL-1β secretion. Loss of autophagy abrogates the inhibitory effect on NLRP3 activation seen upon PTPN22 loss.\",\n      \"method\": \"Autophagosome fractionation, immunofluorescence co-localization with LC3B and LAMP2, siRNA knockdown of ATG7/SQSTM1, pharmacological autophagy inhibition, point mutation (Lys316Arg) of NLRP3\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple approaches (genetic KD, pharmacological inhibition, mutagenesis, imaging), single lab\",\n      \"pmids\": [\"28786745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Autophagy-dependent degradation of PELI3 (an E3 ubiquitin ligase and TLR4-signaling scaffold) attenuates IL1B mRNA expression in macrophages. PELI3 knockdown reduced LPS-induced IL1b expression. SQSTM1/p62 binds PELI3; inhibition of autophagy (via wortmannin, bafilomycin A1, or siRNA against SQSTM1/ATG7) increased PELI3 protein. PELI3 is ubiquitinated after LPS stimulation; mutation of Lys316 to Arg attenuated autophagy-dependent PELI3 degradation. PELI3 co-localized with LC3B and LAMP2 in autophagosomes.\",\n      \"method\": \"siRNA knockdown, pharmacological autophagy inhibition, Co-IP, immunofluorescence, point mutagenesis (Lys316Arg), RT-PCR for Il1b\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in a single lab; direct mechanistic link between PELI3 autophagy and IL1B expression\",\n      \"pmids\": [\"25483963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LIPUS (low-intensity pulsed ultrasound) inhibits mature IL-1β production in LPS/ATP-stimulated macrophages via SQSTM1-dependent autophagic degradation of PKM2. LIPUS upregulated autophagy flux and promoted SQSTM1–PKM2 complex formation; SQSTM1 knockdown reversed LIPUS-induced PKM2 degradation and restored mature IL-1β production.\",\n      \"method\": \"Co-IP (SQSTM1-PKM2), siRNA knockdown of SQSTM1, ELISA for mature IL-1β, autophagy inhibition assays, in vivo DMM mouse model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus knockdown rescue, single lab, in vitro and in vivo\",\n      \"pmids\": [\"31500508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-1β-induced inflammatory gene responses in primary epidermal keratinocytes are entirely dependent on the MyD88 adaptor protein. CRISPR/Cas9 inactivation of MyD88 completely abolished IL-1β (and IL-36G) expression responses of a 225-gene shared cytokine-response signature including upregulation of IL1A, IL1B, IL36G, and inhibitors such as IL1RN.\",\n      \"method\": \"RNA-seq of primary human keratinocytes, CRISPR/Cas9 knockout of MYD88, cytokine stimulation (IL-1B, IL-36A/B/G)\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with genome-wide transcriptomic readout, single lab\",\n      \"pmids\": [\"29434599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In the mouse uterus during early pregnancy, macrophage-derived IL1B (together with LIF) regulates epithelial cell Fut2 mRNA expression and terminal fucosylation of embryo attachment ligands. Neutralizing antibodies to IL1B inhibited macrophage-conditioned medium-stimulated Fut2 upregulation in uterine epithelial cells in vitro; macrophage depletion in vivo reduced UEA-1 and LewisX staining on luminal epithelium.\",\n      \"method\": \"Epithelial cell co-culture with macrophages or conditioned medium, neutralizing antibody blockade of IL1B/LIF, in vivo macrophage depletion (Cd11b-dtr transgenic mice), laser capture microdissection, quantitative RT-PCR, lectin/immunostaining\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro neutralization and in vivo depletion with functional readout, single lab\",\n      \"pmids\": [\"20864644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In porcine uterine endometrium during peri-implantation, IL1B upregulates expression of its own receptor subunits (IL1R1 in a dose-dependent manner, IL1RAP in response to IL1B and estradiol cooperatively) and stimulates expression of prostaglandin-synthetic rate-limiting enzymes PTGS1 and PTGS2.\",\n      \"method\": \"In vitro treatment of porcine uterine endometrial cells with recombinant IL1B, dose-response RT-PCR for IL1R1, IL1RAP, PTGS1, PTGS2\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct in vitro treatment with functional gene-expression readout, single lab, multiple targets measured\",\n      \"pmids\": [\"22572995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IL-1β produced by metastatic ovarian cancer cells induces mesothelial cell β1-integrin expression, facilitating tumor cell adhesion to the peritoneum. Neutralizing antibodies to IL-1β inhibited adhesion of metastatic MFOC3 cells to mesothelial monolayers; recombinant IL-1β enhanced adhesion; anti-β1-integrin antibody inhibited adhesion in vitro and reduced metastases in vivo.\",\n      \"method\": \"Co-culture adhesion assay on mesothelial monolayers, neutralizing antibody blockade, recombinant IL-1β stimulation, anti-β1-integrin blocking antibody, in vivo SCID mouse metastasis model\",\n      \"journal\": \"Journal of ovarian research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal neutralization plus in vivo confirmation, single lab\",\n      \"pmids\": [\"22296757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL1B promoter haplotypes (defined by SNPs at -511, -1464, -3737) predict in vivo IL-1β protein levels in gingival tissue fluid and serum CRP, and validated in stimulated PBMCs: haplotype-pairs associated with higher in vivo IL-1β caused 86–287% more IL-1β production in vitro, demonstrating that individual SNP function is governed by haplotype context affecting IL1B transcription.\",\n      \"method\": \"Haplotype analysis of 900 gingival fluid samples (IL-1β protein by immunoassay), serum CRP, validation in stimulated PBMCs (N=70)\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vivo haplotype-protein correlation validated in independent PBMC stimulation experiment\",\n      \"pmids\": [\"18369665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Low picogram/mL circulating levels of IL-1β combined with IL-6 directly trigger pancreatic islet dysfunction by reducing ER calcium storage, activating ER stress responses (Nos2, Bip, Atf4, Ddit3/CHOP), impairing glucose-stimulated insulin secretion, and increasing cell death—effects that were more severe in islets from prediabetic db/db mice. Subcutaneous osmotic mini-pump delivery of IL-1β+IL-6 in mice reproduced islet calcium handling and secretion defects observed in vitro.\",\n      \"method\": \"In vitro cytokine treatment of isolated mouse and human islets, intracellular calcium imaging, ER calcium measurements, ER stress gene expression, GSIS assay, in vivo osmotic mini-pump cytokine delivery\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo orthogonal approaches in a single lab with multiple mechanistic readouts\",\n      \"pmids\": [\"23836031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL1B triggers SASP production (IL8, IL6, TNFA, CCL2) and upregulates cell adhesion molecule expression in bovine oviduct epithelial cells (OECs). CCL2 induced by IL1B is essential for neutrophil (PMN) migration toward OEC-conditioned medium; CCL2 inhibition, but not IL8/CXCR2 blockade, significantly reduced immune cell migration. IL1B also increased PMN adhesion to OECs, leading to further SASP amplification via direct PMN–OEC interaction.\",\n      \"method\": \"In vitro cytokine treatment of bovine OECs, PMN migration assay with conditioned medium, CCL2/CXCR2 inhibitor blockade, flow cytometry for PMN adhesion\",\n      \"journal\": \"American journal of reproductive immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological receptor blockade identifying CCL2 as the key mediator, single lab, multiple assays\",\n      \"pmids\": [\"33099841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"lnc-HZ06 promotes STAT4-mediated IL1B mRNA transcription and enhances IL1B mRNA stability by promoting formation of a METTL3/HuR/IL1B mRNA ternary complex, upregulating IL-1β levels in BaP/BPDE-exposed trophoblast cells. Knockdown of murine lnc-hz06 (which downregulates Il1b levels) or Il1b directly alleviated miscarriage in BaP-exposed mice. BPDE exposure promotes TBP-mediated lnc-HZ06 transcription upstream of this pathway.\",\n      \"method\": \"siRNA/shRNA knockdown, RIP (RNA immunoprecipitation for METTL3/HuR/IL1B mRNA complex), ChIP for STAT4 at IL1B promoter, in vivo BaP-exposed mouse miscarriage model\",\n      \"journal\": \"Journal of hazardous materials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic steps validated by RIP, ChIP, and in vivo knockdown rescue; single lab\",\n      \"pmids\": [\"38991640\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-1β (IL1B) is a pro-inflammatory cytokine whose expression in monocytes/macrophages depends on Spi-1/PU.1 binding to the IL1B promoter, while in CD4 T cells transcription proceeds from a bivalent promoter independently of Spi-1; mature IL-1β secretion requires NLRP3 inflammasome-mediated processing (regulated by autophagy via PELI3 and PKM2 degradation, and by PTPN22-driven NLRP3 phosphorylation), and downstream signaling through MyD88 mediates its transcriptional responses in target cells such as keratinocytes; IL-1β acts extracellularly to increase intestinal tight junction permeability via MIR200C-3p-dependent occludin mRNA degradation, to induce mesothelial β1-integrin expression facilitating tumor cell adhesion, to regulate uterine Fut2 and prostaglandin synthesis during implantation, and to drive ER stress-mediated pancreatic islet dysfunction and CCL2-dependent neutrophil recruitment in reproductive epithelium.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL1B encodes a pro-inflammatory cytokine whose production is gated at the levels of transcription, post-transcriptional control, and inflammasome-dependent processing, and which then acts extracellularly to remodel epithelial and stromal tissue [#0, #1, #4]. In monocytes/macrophages IL1B is not pre-formed but is induced rapidly upon LPS or monosodium urate crystal stimulation, with transcription depending on binding of the hematopoietic transcription factor Spi-1/PU.1 to two sites in the IL1B promoter [#0, #1]. In CD4 T cells transcription instead proceeds from a bivalent H3K4me3/H3K27me3 promoter independently of Spi-1, yielding cytoplasmic proIL-1\\u03b2 despite low mRNA [#2], while promoter haplotype context quantitatively sets the level of IL-1\\u03b2 produced [#11]. Beyond transcription, IL1B output is constrained by autophagy: autophagic degradation of the TLR4 scaffold PELI3 limits IL1B mRNA expression [#5], degradation of PKM2 limits mature IL-1\\u03b2 production [#6], and PTPN22-driven NLRP3 phosphorylation targets NLRP3 to autophagosomes to suppress inflammasome-mediated secretion [#4]. Secreted IL-1\\u03b2 signals through the MyD88 adaptor to drive inflammatory gene programs, as MyD88 inactivation abolishes the IL-1\\u03b2 transcriptional response in keratinocytes [#7]. Functionally, IL-1\\u03b2 increases intestinal tight-junction permeability by inducing MIR200C-3p, which degrades occludin mRNA [#3], induces mesothelial \\u03b21-integrin to facilitate tumor cell adhesion [#10], triggers ER stress and insulin-secretion defects in pancreatic islets [#12], and drives CCL2-dependent neutrophil recruitment and adhesion-molecule expression in reproductive epithelium [#13]. In reproductive tissue it also regulates uterine Fut2 expression and fucosylation of embryo-attachment ligands and stimulates prostaglandin-synthetic enzymes PTGS1/PTGS2 and its own receptor subunits [#8, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established that IL-1\\u03b2 is an inducible rather than constitutive product, defining the kinetics by which stimulated monocytes accumulate IL1B mRNA, protein, and then secrete it.\",\n      \"evidence\": \"Time-course of IL-1\\u03b2 mRNA and protein in human adherent monocytes after LPS or crystal stimulation\",\n      \"pmids\": [\"1663080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not resolve the transcription factors driving induction\", \"Does not define the processing/secretion machinery\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identified the cell-type-specific transcriptional basis for monocyte IL1B expression by showing Spi-1/PU.1 binds and activates the IL1B promoter.\",\n      \"evidence\": \"Promoter-reporter assays, EMSA, dominant-negative Spi-1, and cotransfection rescue in HeLa cells with site-directed mutagenesis\",\n      \"pmids\": [\"7799967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address regulation in non-myeloid lineages\", \"Does not connect promoter occupancy to signal-induced kinetics\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed that IL1B promoter haplotype context, not single SNPs alone, quantitatively governs in vivo and ex vivo IL-1\\u03b2 production levels.\",\n      \"evidence\": \"Haplotype analysis of gingival fluid IL-1\\u03b2, serum CRP, and stimulated PBMC validation\",\n      \"pmids\": [\"18369665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative for individual SNP mechanism\", \"Does not identify the transcription factors whose binding the haplotypes alter\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed lineage-divergent IL1B regulation by demonstrating Spi-1-independent, bivalent-chromatin-poised transcription in CD4 T cells distinct from monocytes.\",\n      \"evidence\": \"ChIP for H3K4me3/H3K27me3, RT-PCR, and immunoblot of proIL-1\\u03b2 in CD3/CD28-activated primary human CD4 T cells\",\n      \"pmids\": [\"30300855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the T-cell-specific activating transcription factors\", \"Does not establish whether T-cell proIL-1\\u03b2 is processed and secreted\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined autophagy as a brake on IL1B mRNA expression by showing SQSTM1-mediated autophagic degradation of the TLR4 scaffold PELI3.\",\n      \"evidence\": \"siRNA knockdown, autophagy inhibition, Co-IP, Lys316Arg mutagenesis, and RT-PCR in macrophages\",\n      \"pmids\": [\"25483963\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Does not quantify contribution relative to other PELI3-independent pathways\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked PTPN22 to inflammasome control by showing PTPN22 loss increases NLRP3 phosphorylation, routing NLRP3 to autophagic degradation and suppressing IL-1\\u03b2 secretion.\",\n      \"evidence\": \"Autophagosome fractionation, LC3B/LAMP2 co-localization, ATG7/SQSTM1 knockdown, autophagy inhibition, and NLRP3 K316R mutation\",\n      \"pmids\": [\"28786745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Kinase responsible for NLRP3 phosphorylation downstream of PTPN22 not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended autophagic control to mature cytokine output by showing SQSTM1-dependent degradation of PKM2 suppresses mature IL-1\\u03b2 production.\",\n      \"evidence\": \"SQSTM1-PKM2 Co-IP, siRNA knockdown rescue, ELISA, and an in vivo DMM mouse model under LIPUS\",\n      \"pmids\": [\"31500508\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism connecting PKM2 levels to inflammasome processing not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established MyD88 as the obligate adaptor for IL-1\\u03b2 signal transduction in target epithelium.\",\n      \"evidence\": \"RNA-seq with CRISPR/Cas9 MYD88 knockout in primary human keratinocytes under IL-1\\u03b2 stimulation\",\n      \"pmids\": [\"29434599\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Restricted to keratinocytes\", \"Does not dissect downstream NF-\\u03baB versus other branches\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated a tissue-remodeling role for IL-1\\u03b2 in reproduction by showing macrophage-derived IL1B regulates uterine epithelial Fut2 and fucosylation of attachment ligands.\",\n      \"evidence\": \"Epithelial-macrophage co-culture, IL1B neutralization, in vivo Cd11b-dtr macrophage depletion, LCM, and lectin staining in mouse uterus\",\n      \"pmids\": [\"20864644\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish the receptor/signaling route in epithelium\", \"Co-dependency with LIF not fully separated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed IL-1\\u03b2 amplifies its own signaling and prostaglandin synthesis in peri-implantation endometrium, and separately that tumor-derived IL-1\\u03b2 promotes peritoneal metastatic adhesion via mesothelial \\u03b21-integrin.\",\n      \"evidence\": \"Recombinant IL1B dose-response RT-PCR in porcine endometrium; co-culture adhesion assays, IL-1\\u03b2 and \\u03b21-integrin neutralization, and SCID mouse metastasis model\",\n      \"pmids\": [\"22572995\", \"22296757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endometrial work is porcine and gene-expression-level only\", \"Adhesion mechanism does not define the IL-1\\u03b2 receptor signaling step in mesothelium\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that low circulating IL-1\\u03b2, acting with IL-6, drives ER-stress-mediated pancreatic islet dysfunction and impaired insulin secretion.\",\n      \"evidence\": \"Cytokine treatment of mouse/human islets with calcium imaging, ER stress gene profiling, GSIS, and in vivo osmotic mini-pump delivery\",\n      \"pmids\": [\"23836031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cannot isolate IL-1\\u03b2 from IL-6 contribution\", \"Receptor and signaling intermediates in \\u03b2-cells not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined two distinct effector mechanisms: IL-1\\u03b2 disrupts intestinal barrier integrity via MIR200C-3p-mediated occludin mRNA degradation, and recruits neutrophils via CCL2 in reproductive epithelium.\",\n      \"evidence\": \"Caco-2 permeability with antagomiR and in vivo perfusion plus miRNA-mRNA structural modeling; bovine OEC PMN-migration assays with CCL2/CXCR2 blockade\",\n      \"pmids\": [\"32569770\", \"33099841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not link these effector outputs back to IL-1\\u03b2 receptor/MyD88 signaling explicitly\", \"CCL2 work is bovine\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a post-transcriptional amplifier of IL1B in trophoblasts whereby lnc-HZ06 promotes STAT4-driven transcription and METTL3/HuR-mediated mRNA stabilization, linking IL-1\\u03b2 dysregulation to miscarriage.\",\n      \"evidence\": \"RIP for the METTL3/HuR/IL1B complex, ChIP for STAT4, and in vivo lnc-hz06/Il1b knockdown rescue in BaP-exposed mice\",\n      \"pmids\": [\"38991640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Generality of lnc-HZ06 control beyond toxicant-exposed trophoblasts unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the divergent transcriptional inputs, autophagy-based brakes, and inflammasome processing are integrated in a single cell to set the quantitative threshold and timing of mature IL-1\\u03b2 release remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified quantitative model of transcription-to-secretion flux\", \"Receptor-proximal signaling for most effector phenotypes not mapped within the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [7, 10, 12, 3, 13]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 4, 7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MYD88\", \"IL1R1\", \"IL1RAP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}