Affinage

IL1A

Interleukin-1 alpha · UniProt P01583

Audit flag: wrong gene
Length
271 aa
Mass
30.6 kDa
Annotated
2026-06-10
100 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL-1α is a pleiotropic pro-inflammatory cytokine whose precursor is constitutively expressed in epithelial and myeloid cells and which signals through the type I IL-1 receptor (IL-1R1) to drive NF-κB- and MAPK-dependent inflammatory programs (PMID:3258334, PMID:22031183). The receptor, a three-immunoglobulin-domain protein that binds IL-1α and IL-1β indistinguishably, initiates signaling by recruiting the accessory protein IL-1RAcP to assemble a signaling-competent heterotrimeric complex (PMID:2969618, PMID:22426547). Downstream, the IL-1R1 cytoplasmic domain engages the kinases IRAK and NIK to activate NF-κB, while directly associating with RhoA and Rac-1 to couple receptor engagement to actin stress fiber formation and amplified NF-κB/IL-6 transcription (PMID:9020361, PMID:10359565, PMID:10754329). IL-1α expression and processing are controlled at multiple levels: keratinocyte transcription is constitutive and modulated by LPS, UV, and differentiation state (PMID:3258334); calpain cleaves the precursor with efficiency that depends on a coding polymorphism (PMID:17440718); and mTOR/TORC1 selectively promotes IL-1α translation in senescent cells to drive NF-κB-dependent SASP cytokine secretion (PMID:26147250). Through IL-1R1, IL-1α governs diverse tissue processes including paracrine S100A8/A9-mediated keratinocyte antibacterial defense (PMID:22031183), blood-testis barrier restructuring via actin reorganization (PMID:18057314), thymocyte CD25 induction and T cell lineage commitment (PMID:7541554), central hypothalamic restraint of bone resorption (PMID:16126903), and TNF-induced RANKL-dependent osteoclastogenesis (PMID:15668736). In aging, myeloid-derived IL-1α driven by microbial signals and DNMT3A decline acts on IL-1R1 on hematopoietic stem/progenitor cells to promote myeloid-biased aging, clonal expansion of TET2-mutant clones, emergency myelopoiesis, and tumor progression (PMID:34525198, PMID:36379023, PMID:39236155). A gain-of-function IL-1R1 variant that abolishes IL-1Ra binding causes the autoinflammatory disease CRMO, underscoring the pathological consequence of unopposed IL-1 signaling (PMID:37315560).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1988 High

    Establishing the molecular identity of the IL-1 receptor defined how IL-1α and IL-1β share a single signaling entry point.

    Evidence cDNA expression cloning from mouse T cells with receptor-binding validation

    PMID:2969618

    Open questions at the time
    • Did not resolve how the receptor distinguishes agonist from antagonist
    • Cytoplasmic signaling machinery not yet defined
    • No accessory subunit identified
  2. 1988 Medium

    Demonstrating constitutive, condition-responsive IL-1α expression in keratinocytes established epithelial cells as a source of IL-1α independent of IL-1β.

    Evidence Northern blotting and IL-1 bioassay in keratinocyte culture under defined Ca²⁺ and LPS/UV conditions

    PMID:3258334

    Open questions at the time
    • Mechanism linking differentiation state to expression unresolved
    • Did not define release or signaling consequences
  3. 1989 Medium

    Chronic in vivo IL-1α exposure was shown to drive selective skeletal muscle protein catabolism, defining a systemic catabolic action.

    Evidence Chronic cytokine administration in rats with protein fractionation and muscle mRNA Northern blotting

    PMID:2784290

    Open questions at the time
    • Receptor/signaling pathway mediating muscle wasting not identified
    • Tissue selectivity mechanism unknown
  4. 1990 Medium

    Internalization of the IL-1α–receptor complex into nuclei and the regulation of IL-1β bioactivity by α2-macroglobulin sequestration revealed post-binding control of IL-1 action.

    Evidence 125I-IL-1 internalization with EM autoradiography and nuclear fractionation; native PAGE binding/release assays with thioredoxin and bioassays

    PMID:1700994 PMID:2137488

    Open questions at the time
    • Functional role of nuclear receptor translocation not established
    • Physiological relevance of α2M sequestration in vivo unresolved
  5. 1991 Medium

    Chromosomal mapping placed IL1A, IL1B, and IL1R1 in proximity on human 2q, framing the genomic organization of the IL-1 system.

    Evidence Hybrid cell segregation, in situ hybridization, and RFLP analysis in human and mouse

    PMID:1672292

    Open questions at the time
    • No functional consequence of genomic clustering established
    • Regulatory linkage not addressed
  6. 1995 Medium

    Identifying IL-1α as necessary for thymocyte CD25 induction and CD4/CD8 differentiation extended IL-1α function to T cell development.

    Evidence Thymus reconstitution in irradiated mice with flow cytometry and cytokine neutralization epistasis

    PMID:7541554

    Open questions at the time
    • Did not separate IL-1α from TNF-α requirement molecularly
    • Receptor-level signaling in thymocytes not dissected
  7. 1997 High

    Placing NIK in the IL-1-to-NF-κB cascade identified a shared kinase node converging IL-1, TNF, and CD95 signaling onto NF-κB.

    Evidence Yeast two-hybrid and dominant-negative kinase expression with NF-κB reporter assays

    PMID:9020361

    Open questions at the time
    • Precise position relative to IRAK not resolved here
    • Endogenous requirement not tested genetically in this study
  8. 1998 High

    Demonstrating a paracrine IL-1 → iNOS → NO axis in pancreatic islets established IL-1α as a driver of beta-cell dysfunction.

    Evidence RT-PCR, macrophage colocalization, IL-1Ra blockade, iNOS inhibition, and insulin secretion assays in human islets

    PMID:9691088

    Open questions at the time
    • Relative contribution of IL-1α vs IL-1β not separated
    • Long-term beta-cell fate not addressed
  9. 1999 High

    Discovery that the IL-1R cytoplasmic domain directly binds RhoA/Rac-1 connected receptor engagement to cytoskeletal remodeling and transcriptional output.

    Evidence GST pulldown, Co-IP, C3 transferase, dominant-inhibitory RhoA, IL-6 promoter reporter, and gel kinase assays

    PMID:10359565

    Open questions at the time
    • Adaptor bridging receptor to RhoA not defined
    • Reciprocal in vivo validation absent
  10. 2000 High

    Genetic ablation of IRAK established it as an essential signaling mediator shared between IL-1/IL-18 and TLR pathways.

    Evidence IRAK knockout macrophages and in vivo LPS lethality model with TNF-α production readouts

    PMID:10754329

    Open questions at the time
    • IL-1α-specific (vs IL-1β/TLR) requirement not isolated
    • Downstream substrate connections not mapped here
  11. 2002 Medium

    Linking IL-1α transcription to MyD88 revealed pathogen-driven upstream regulation while uncoupling mRNA induction from protein output.

    Evidence Promoter-luciferase reporter, dominant-negative MyD88, MyD88−/− macrophages, RT-PCR and ELISA after L. major infection

    PMID:12270723

    Open questions at the time
    • Translational/processing block preventing protein accumulation not identified
    • Single pathogen context
  12. 2005 High

    Two studies defined IL-1's role in bone homeostasis: peripherally driving TNF-induced RANKL/osteoclastogenesis and centrally restraining bone resorption via hypothalamic IL-1R1.

    Evidence IL-1RI-knockout stromal cells, co-culture osteoclastogenesis, p38 inhibition, and CNS-targeted IL-1Ra transgenic mice with bone histomorphometry

    PMID:15668736 PMID:16126903

    Open questions at the time
    • IL-1α vs IL-1β contribution to each arm not separated
    • Neural circuitry of central restraint undefined
  13. 2007 Medium

    Two studies established IL-1α's regulation of the blood-testis barrier via actin reorganization and a coding SNP controlling calpain processing efficiency.

    Evidence Intratesticular IL-1α injection with BTB integrity, immunolocalization, and phalloidin staining; calpain titration of fibroblast lysates with defined +4845 genotypes

    PMID:17440718 PMID:18057314

    Open questions at the time
    • Signaling pathway from IL-1R1 to actin in Sertoli cells not mapped
    • Clinical impact of processing-efficiency SNP not functionally proven in vivo
  14. 2011 High

    Defining the IL-1α → IL-1R → S100A8/A9 paracrine axis established a mechanism for epithelial antibacterial defense.

    Evidence L. monocytogenes infection, conditioned media transfer, IL-1R antagonist, and S100A8/A9 shRNA knockdown with bacterial quantification

    PMID:22031183

    Open questions at the time
    • Mode of IL-1α release from infected cells not defined
    • Generalizability beyond Listeria untested
  15. 2012 High

    The crystal structure of the IL-1β/IL-1RI/IL-1RAcP complex defined the heterotrimeric receptor assembly that initiates IL-1-type signaling.

    Evidence X-ray crystallography of the ternary signaling complex

    PMID:22426547

    Open questions at the time
    • Structure solved with IL-1β rather than IL-1α
    • Cytoplasmic assembly of adaptors not captured
  16. 2015 High

    Identifying mTOR-dependent translational control of membrane IL-1α positioned IL-1α as the upstream NF-κB driver of the senescence-associated secretory phenotype.

    Evidence Rapamycin treatment with IL-1α protein/mRNA quantification, NF-κB reporter, cytokine ELISA, and exogenous IL-1α rescue in senescent fibroblasts

    PMID:26147250

    Open questions at the time
    • Mechanism of selective IL-1α mRNA translation not resolved
    • In vivo SASP relevance only partially addressed
  17. 2022 High

    Defining the microbiome/IL-1/IL-1R1 axis established myeloid-derived IL-1α as a driver of hematopoietic stem cell inflammaging.

    Evidence IL-1R1 knockout, germ-free and antibiotic-treated mice, bone marrow transplantation, and HSC transcriptomics

    PMID:34525198

    Open questions at the time
    • IL-1α vs IL-1β specific contribution not fully separated
    • Molecular events downstream of IL-1R1 in HSCs not detailed
  18. 2023 High

    Two studies established the IL-1/IL-1R1 axis as a driver of TET2-mutant clonal hematopoiesis and identified a CRMO-causing gain-of-function IL-1R1 variant that abolishes antagonist binding.

    Evidence Tet2+/− mosaic mouse models with IL-1α administration and IL-1R1 conditional knockout; patient genetics, mutant receptor binding assays, mouse arthritis model, and structure-guided drug design

    PMID:36379023 PMID:37315560

    Open questions at the time
    • Whether IL-1α or IL-1β dominates clonal expansion not resolved
    • Human therapeutic efficacy of antagonist-sparing trap not yet clinically validated
  19. 2024 High

    Linking age-associated DNMT3A decline to IL-1α-driven emergency myelopoiesis connected hematopoietic aging to tumor progression across cancer types.

    Evidence Hematopoietic aging chimeras, DNMT3A loss-of-function, IL-1R1 genetic disruption, multiple tumor models, and human tumor single-cell analysis

    PMID:39236155

    Open questions at the time
    • Mechanism by which DNMT3A loss enhances IL-1α specifically not detailed
    • Translation to human therapy not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct activities of IL-1α — nuclear/precursor alarmin functions, calpain-dependent processing, and receptor-mediated signaling — are integrated and differentiated from IL-1β at the cellular level remains unresolved.
  • Most in vivo studies do not separate IL-1α from IL-1β contributions
  • Functional role of nuclear IL-1α localization uncharacterized
  • Direct structure of the IL-1α (vs IL-1β) ternary receptor complex not in corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 1 GO:0005634 nucleus 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-8953897 Cellular responses to stimuli 1
Partners
A2MIL1R1IL1RAPIRAK1MAP3K14RAC1RHOA
Complex memberships
IL-1α/IL-1R1/IL-1RAcP signaling complex

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 The IL-1 receptor was cloned by direct expression strategy from mouse T cells; the receptor binds both IL-1α and IL-1β, has an extracellular domain of 319 amino acids composed of three immunoglobulin-like domains, and a cytoplasmic domain of 217 amino acids. The cloned receptor product binds IL-1α and IL-1β indistinguishably from the native T cell IL-1R. cDNA expression cloning, receptor-binding assay Science High 2969618
1988 Murine keratinocytes constitutively express IL-1α mRNA (but not IL-1β mRNA). LPS exposure increased IL-1α mRNA >10-fold with a sixfold increase in secreted IL-1 activity. UV irradiation modulated IL-1α expression in a dose-dependent manner. IL-1α expression decreased with terminal keratinocyte differentiation (high Ca²⁺) and increased with undifferentiated state (low Ca²⁺). Northern blotting, IL-1 bioassay, keratinocyte culture under defined Ca²⁺ conditions Journal of Immunology Medium 3258334
1989 Chronic in vivo administration of IL-1α produced protein wasting with accelerated peripheral skeletal muscle protein loss while preserving liver protein content, a pattern distinct from simple caloric restriction. Decrease in skeletal muscle protein was accompanied by coordinate decreases in mRNAs for myosin heavy chain, myosin light chain, actin, and ribosomal RNA subunits. In vivo chronic cytokine administration in rats, protein fractionation, Northern blotting for muscle mRNAs American Journal of Physiology Medium 2784290
1990 Internalized IL-1α remains bound to its receptor intracellularly for at least 4 hours without degradation, and accumulates in purified nuclei as an IL-1–receptor complex. No IL-1 receptors were detected in untreated nuclei, suggesting IL-1-driven translocation of the cell surface IL-1R complex to the nucleus. This internalization correlated with IL-1 signal transduction events required for growth factor production. 125I-IL-1α internalization, electron microscope autoradiography, nuclear fractionation, receptor-binding in isolated nuclei Journal of Immunology Medium 2137488
1990 IL-1β binds to human alpha-2-macroglobulin (H-α2M) forming a complex in a pH- and divalent cation-dependent (Zn²⁺, Cd²⁺, Cu²⁺, Ni²⁺) manner. H-α2M-bound IL-1β is partially biologically inactive; reduced thioredoxin releases bound IL-1β and restores IL-1-like bioactivity. Binding requires histidyl residues in H-α2M. 125I-IL-1β binding assay, native PAGE, competition assay, thioredoxin release assay, two independent bioassays Journal of Immunology Medium 1700994
1991 The human IL-1R1 gene was mapped to chromosome 2q12, near the IL-1α and IL-1β loci at 2q13–2q21. The murine Il-1r1 gene was mapped to chromosome 1, showing synteny with human chromosome 2 but separated from the murine IL-1 genes on chromosome 2. Rodent-human hybrid cell segregation analysis, chromosomal in situ hybridization, restriction fragment length polymorphism analysis in interspecific backcrosses Genomics Medium 1672292
1995 TNF-α and IL-1α, produced within the thymic microenvironment, are each necessary for early thymocyte maturation and CD4+CD8+ differentiation. Either cytokine induced CD25 expression on early immature thymocytes in a thymus reconstitution assay; absence of both (or either) blocked further T cell lineage commitment. Thymus reconstitution assay in irradiated mice, flow cytometry for CD25/CD4/CD8, genetic epistasis with cytokine neutralization Science Medium 7541554
1997 NIK (NF-κB-inducing kinase) was identified as a MAP3K-related kinase that participates in NF-κB induction by IL-1. Expression of kinase-deficient NIK mutants blocked NF-κB induction by IL-1 (as well as by TNF and CD95 signaling), establishing NIK as part of a common NF-κB-inducing signaling cascade downstream of the IL-1 type-I receptor. Yeast two-hybrid (Traf2 binding), expression of dominant-negative kinase mutants in cells, NF-κB reporter assays Nature High 9020361
1998 IL-1α and IL-1β are produced by resident macrophages within human islets of Langerhans in response to TNF + LPS + IFN-γ stimulation. Endogenously released IL-1 drives iNOS expression and nitric oxide production in beta cells, resulting in inhibition of glucose-stimulated insulin secretion. The IL-1 receptor antagonist protein (IRAP) blocked these effects, demonstrating a paracrine IL-1 → iNOS → NO → insulin secretion inhibition axis. RT-PCR for IL-1α/β mRNA, immunohistochemical colocalization with CD69 macrophage marker, IL-1Ra blockade, aminoguanidine (iNOS inhibitor), nitrite assay, insulin secretion assay Journal of Clinical Investigation High 9691088
1999 The cytoplasmic domain of IL-1R type I (IL-1Rcd) directly associates with RhoA and Rac-1 (but not p21Ras). IL-1 stimulation rapidly activates nucleotide exchange on RhoA and induces actin stress fiber formation in a Rho-dependent manner. RhoA association with IL-1Rcd is required for IL-1-directed NF-κB/IL-6 transcriptional activation and for IL-1R-associated MBP kinase activity. GST pulldown of RhoA/Rac-1 from cell extracts, coimmunoprecipitation with anti-IL-1R antibody, C3 transferase ADP-ribosylation assay, dominant-inhibitory RhoA transfection, reporter gene (IL-6 promoter), gel kinase assay Journal of Clinical Investigation High 10359565
2000 IRAK (IL-1 receptor-associated kinase) is activated by LPS in macrophages through a TLR4-dependent mechanism. IRAK-deficient macrophages are resistant to LPS-induced signaling and show impaired TNF-α production. IRAK-deficient mice withstand lethal LPS challenge, establishing IRAK as a critical signaling mediator shared between the IL-1/IL-18 receptor and TLR pathways. IRAK knockout macrophages, LPS stimulation, signaling cascade analysis, TNF-α production assay, in vivo LPS lethality model Journal of Immunology High 10754329
2002 Leishmania major activates IL-1α promoter activity and mRNA expression in macrophages through a MyD88-dependent pathway. Dominant-negative MyD88 transfection and peritoneal macrophages from MyD88−/− mice both showed inhibited IL-1α promoter/mRNA responses to L. major. Despite mRNA induction, no IL-1α protein was detectable in cell lysates or supernatants, indicating additional anti-inflammatory pathways suppress IL-1α translation. Cytokine promoter-luciferase reporter transfection, dominant-negative MyD88 expression, MyD88−/− knockout macrophages, RT-PCR, ELISA Microbes and Infection Medium 12270723
2005 TNF induces stromal cell expression of IL-1 and IL-1 receptor type I (IL-1RI). IL-1 (both α and β forms) then mediates TNF-induced RANKL expression by bone marrow stromal cells and directly stimulates osteoclast precursor differentiation via p38 MAPK, accounting for ~50% of TNF-induced osteoclastogenesis. IL-1Ra or IL-1RI deficiency abolished this TNF→IL-1→RANKL pathway. IL-1Ra treatment, IL-1RI-knockout stromal cells, co-culture osteoclastogenesis assay, in vivo TNF administration to IL-1RI-KO mice, p38 MAPK inhibition Journal of Clinical Investigation High 15668736
2005 Central IL-1 receptor signaling via hypothalamic IL-1RI normally restrains bone resorption; IL-1RI-deficient mice and mice with CNS-targeted IL-1Ra overexpression (under GFAP promoter) both exhibited low bone mass and impaired bone growth characterized by doubled osteoclast number. This phenotype occurred without changes in testosterone or corticosterone, suggesting a neural pathway distinct from the HPA and gonadal axes. IL-1RI knockout mice, CNS-targeted IL-1Ra transgenic mice (GFAP promoter), bone histomorphometry, serum hormone measurements Proceedings of the National Academy of Sciences High 16126903
2007 Intratesticular administration of IL-1α in adult rats disrupted blood-testis barrier (BTB) integrity and caused Sertoli-germ cell adhesion loss without altering steady-state levels of BTB proteins (OCLN, CLDN1, F11R, TJP1, CDH2). Instead, IL-1α altered the subcellular localizations of OCLN, F11R, and TJP1 away from cell-cell contact sites and disrupted the orderly arrangement of filamentous actin at the BTB and apical ectoplasmic specialization. Intratesticular IL-1α injection, inulin-FITC BTB integrity assay, Western blotting, immunofluorescence localization, phalloidin staining for F-actin Biology of Reproduction Medium 18057314
2007 The SNP at position +4845 of IL1A (G/T, encoding Ala or Ser at amino acid 114 of precursor IL-1α) affects enzymatic efficiency of calpain in cleaving precursor IL-1α. A 100-fold higher calpain concentration was required to process pre-IL-1α containing Ala (GG genotype, enriched in SSc patients) compared to Ser (TT genotype). The -889 C/T promoter SNP did not significantly affect transcriptional activity in fibroblasts. Luciferase reporter assay for promoter SNP, Western blotting after calpain titration of cell lysates from fibroblasts with defined +4845 genotypes Immunogenetics Medium 17440718
2011 Listeria-infected epithelial cells release IL-1α, which signals neighboring keratinocytes in a paracrine manner through the IL-1 receptor to upregulate S100A8/A9 expression and confer resistance to bacterial invasion. shRNA knockdown of S100A8/A9 reversed IL-1α-mediated resistance, establishing the IL-1α → IL-1R → S100A8/A9 axis as the mechanism of keratinocyte antibacterial defense. L. monocytogenes infection assay, conditioned media transfer, IL-1R antagonist blockade, shRNA knockdown of S100A8/A9, intracellular bacterial quantification Mucosal Immunology High 22031183
2012 Crystal structure of the IL-1β–IL-1RI–IL-1RAcP signaling complex was determined, revealing that IL-1-type cytokines initiate signaling by binding a primary receptor that recruits an accessory protein to form a signaling-competent heterotrimeric complex, and establishing an evolutionary relationship between IL-1R and fibroblast growth factor receptor family. X-ray crystallography of the ternary IL-1β/IL-1RI/IL-1RAcP complex Nature Structural & Molecular Biology High 22426547
2015 mTOR/TORC1 selectively promotes translation of membrane-bound IL-1α in senescent cells. Rapamycin suppressed IL-1α translation (but not mRNA levels), thereby reducing NF-κB transcriptional activity and downstream SASP cytokine secretion (IL-6 and others). Exogenous IL-1α restored IL-6 secretion in rapamycin-treated senescent cells, establishing IL-1α as a key upstream regulator of the SASP through NF-κB. Rapamycin treatment, IL-1α protein/mRNA quantification, cytokine ELISA, NF-κB reporter assay, exogenous IL-1α rescue experiment, in vivo tumor growth assay with senescent fibroblasts Nature Cell Biology High 26147250
2022 Aging bone marrow myeloid cells produce increasing amounts of IL-1α and IL-1β in steady state; exposure to microbial products (TLR4/TLR8 ligands from gut microbiota) drives this IL-1 production. Signaling through IL-1R1 on hematopoietic stem cells drives myeloid-biased aging phenotype. IL-1R1 knockout mice, germ-free mice, antibiotic treatment, or pharmacologic IL-1 blockade all reversed myeloid-biased HSC output, establishing the microbiome/IL-1/IL-1R1 axis as a driver of HSC inflammaging. IL-1R1 knockout mice, germ-free mice, antibiotic treatment, in vitro cytokine stimulation, bone marrow transplantation, transcriptomic analysis of HSCs Blood High 34525198
2023 IL-1α (and IL-1β) signaling through IL-1R1 drives clonal expansion of Tet2+/− hematopoietic stem and progenitor cells (HSPCs) during aging. IL-1α treatment increased Tet2+/− HSPC cell cycle progression, multilineage differentiation, and repopulation capacity relative to wild-type HPSCs. Genetic deletion of IL-1R1 in Tet2+/− HSPCs or pharmacologic IL-1 inhibition impaired Tet2+/− clonal expansion, establishing the IL-1/IL-1R1 axis as a therapeutically targetable driver of TET2-mutant clonal hematopoiesis. Bone marrow transplantation, genetic mosaicism mouse model (HSC-SCL-Cre-ERT; Tet2+/flox), IL-1α administration, IL-1R1 conditional knockout, pharmacologic IL-1 inhibition, cell cycle analysis, transcriptomic analysis Blood High 36379023
2023 A de novo gain-of-function missense variant in IL-1R1 (p.Lys131Glu) disrupts binding of the antagonist IL-1Ra but not IL-1α or IL-1β, resulting in unopposed IL-1 signaling and autoinflammation (CRMO). Mice with the homologous mutation showed hyperinflammation and pathological osteoclastogenesis. This structural insight was used to design an IL-1 therapeutic that traps IL-1α and IL-1β but spares IL-1Ra. Patient PBMC transcriptomics, mutant mouse model, binding assays for IL-1Ra/IL-1α/IL-1β to mutant receptor, collagen antibody-induced arthritis model, structure-guided drug design Immunity High 37315560
2024 Age-associated decline of DNA methyltransferase 3A (DNMT3A) in hematopoietic myeloid progenitor-like cells enhances IL-1α production. These cells accumulate in lung tumors with aging and drive emergency myelopoiesis via IL-1α. Disrupting IL-1R1 signaling early in tumor development normalized myelopoiesis and slowed lung, colonic, and pancreatic tumor growth. Hematopoietic aging chimera experiments, DNMT3A loss-of-function, IL-1α quantification, IL-1R1 genetic disruption, tumor growth assays in multiple cancer models, human tumor single-cell analysis Science High 39236155

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Overview of the IL-1 family in innate inflammation and acquired immunity. Immunological reviews 1437 29247995
1997 MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature 1121 9020361
2015 MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nature cell biology 922 26147250
2006 The P2X7 receptor: a key player in IL-1 processing and release. Journal of immunology (Baltimore, Md. : 1950) 871 16547218
1988 cDNA expression cloning of the IL-1 receptor, a member of the immunoglobulin superfamily. Science (New York, N.Y.) 863 2969618
2010 Disease-associated functions of IL-33: the new kid in the IL-1 family. Nature reviews. Immunology 825 20081870
2010 Interleukin-1 (IL-1) pathway. Science signaling 778 20086235
2018 NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis. Circulation research 723 29880500
2010 IL-1 pathways in inflammation and human diseases. Nature reviews. Rheumatology 722 20177398
2008 IL-1, IL-18, and IL-33 families of cytokines. Immunological reviews 707 18613828
2005 IL-1 mediates TNF-induced osteoclastogenesis. The Journal of clinical investigation 583 15668736
2002 The balance between IL-1 and IL-1Ra in disease. Cytokine & growth factor reviews 579 12220547
2002 The IL-1 family and inflammatory diseases. Clinical and experimental rheumatology 502 14989423
1989 Cachectin/TNF or IL-1 alpha induces cachexia with redistribution of body proteins. The American journal of physiology 312 2784290
2016 IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis. The Journal of allergy and clinical immunology 298 28043870
2019 The IL-1 family of cytokines and receptors in rheumatic diseases. Nature reviews. Rheumatology 271 31515542
2019 Structural Basis of IL-1 Family Cytokine Signaling. Frontiers in immunology 239 31281320
2014 IL-1 blockade in autoinflammatory syndromes. Annual review of medicine 236 24422572
2000 IL-1 receptor-associated kinase modulates host responsiveness to endotoxin. Journal of immunology (Baltimore, Md. : 1950) 219 10754329
2012 Caspase-1: is IL-1 just the tip of the ICEberg? Cell death & disease 218 22764097
1998 IL-1 produced and released endogenously within human islets inhibits beta cell function. The Journal of clinical investigation 211 9691088
2018 The IL-1 Pathway Is Hyperactive in Hidradenitis Suppurativa and Contributes to Skin Infiltration and Destruction. The Journal of investigative dermatology 199 30528824
2012 IL-1 receptor 2 (IL-1R2) and its role in immune regulation. Brain, behavior, and immunity 198 23195532
2014 The role IL-1 in tumor-mediated angiogenesis. Frontiers in physiology 190 24734023
2014 LPS and IL-1 differentially activate mouse and human astrocytes: role of CD14. Glia 174 24659539
1990 IL-1 and its receptor are translocated to the nucleus. Journal of immunology (Baltimore, Md. : 1950) 171 2137488
1998 Sleep. A physiologic role for IL-1 beta and TNF-alpha. Annals of the New York Academy of Sciences 161 9917875
2014 The TLR and IL-1 signalling network at a glance. Journal of cell science 160 24829146
2004 Therapeutic strategies to reduce IL-1 activity in treating local and systemic inflammation. Current opinion in pharmacology 154 15251132
2004 T1/ST2--an IL-1 receptor-like modulator of immune responses. Cytokine & growth factor reviews 146 15110792
2012 Targeting IL-1 in depression. Expert opinion on therapeutic targets 138 22925041
2014 IL-1 signaling in obesity-induced hepatic lipogenesis and steatosis. PloS one 136 25216251
2006 IL-1 receptor antagonist in metabolic diseases: Dr Jekyll or Mr Hyde? FEBS letters 134 17097645
2023 Aging drives Tet2+/- clonal hematopoiesis via IL-1 signaling. Blood 133 36379023
2022 IL-1 mediates microbiome-induced inflammaging of hematopoietic stem cells in mice. Blood 133 34525198
2009 Regulating human Th17 cells via differential expression of IL-1 receptor. Blood 124 19965648
2019 IL-1 and TNFα Contribute to the Inflammatory Niche to Enhance Alveolar Regeneration. Stem cell reports 122 30930244
2013 IL-1 and T Helper Immune Responses. Frontiers in immunology 122 23874332
1995 Requirement for TNF-alpha and IL-1 alpha in fetal thymocyte commitment and differentiation. Science (New York, N.Y.) 120 7541554
2019 IL-1 in osteoarthritis: time for a critical review of the literature. F1000Research 118 31249675
1994 The IL-1 receptor signaling pathway. Journal of leukocyte biology 118 7964161
1999 The IL-1 receptor and Rho directly associate to drive cell activation in inflammation. The Journal of clinical investigation 117 10359565
1988 The expression and modulation of IL-1 alpha in murine keratinocytes. Journal of immunology (Baltimore, Md. : 1950) 117 3258334
2024 Hematopoietic aging promotes cancer by fueling IL-1⍺-driven emergency myelopoiesis. Science (New York, N.Y.) 113 39236155
2018 IL-1 Family Cytokine Pathways Underlying NAFLD: Towards New Treatment Strategies. Trends in molecular medicine 113 29665983
2020 The IL-1 family cytokines and receptors in autoimmune diseases. Autoimmunity reviews 100 32663626
2012 Structure of the activating IL-1 receptor signaling complex. Nature structural & molecular biology 98 22426547
2012 Inflammasome activation of IL-1 family mediators in response to cutaneous photodamage. Photochemistry and photobiology 85 22631445
2020 IL-1 Signaling in Tumor Microenvironment. Advances in experimental medicine and biology 83 32060884
2016 IL-1 Inhibition and Vascular Function in CKD. Journal of the American Society of Nephrology : JASN 79 27647856
2005 Interleukin (IL)-1A and IL-6: applications to the predictive diagnostic testing of radiation pneumonitis. International journal of radiation oncology, biology, physics 79 15850931
2013 Negative regulatory receptors of the IL-1 family. Seminars in immunology 77 24239046
2020 Blocking IL-1 to prevent respiratory failure in COVID-19. Critical care (London, England) 76 32682440
2013 Autophagy and IL-1 Family Cytokines. Frontiers in immunology 76 23577011
1991 Chromosomal location of murine and human IL-1 receptor genes. Genomics 71 1672292
2021 The Immunological Impact of IL-1 Family Cytokines on the Epidermal Barrier. Frontiers in immunology 70 35003136
2020 IL-1 Superfamily Members and Periodontal Diseases. Journal of dental research 70 32758110
2017 Inflammasomes and IL-1 biology in the pathogenesis of allograft dysfunction. The Journal of clinical investigation 70 28569730
2007 Interleukin 1 alpha (IL1A) is a novel regulator of the blood-testis barrier in the rat. Biology of reproduction 70 18057314
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1989 Rabbit IL-1. Cloning, expression, biologic properties, and transcription during endotoxemia. Journal of immunology (Baltimore, Md. : 1950) 67 2784458
2004 Anakinra: an inhibitor of IL-1 for the treatment of rheumatoid arthritis. Expert opinion on biological therapy 64 15268666
2021 IL-1 Family Antagonists in Mouse and Human Skin Inflammation. Frontiers in immunology 63 33796114
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1999 TNF alpha and IL-1 beta are separate targets in chronic arthritis. Clinical and experimental rheumatology 62 10589368
2023 Identification of an IL-1 receptor mutation driving autoinflammation directs IL-1-targeted drug design. Immunity 61 37315560
2002 Leishmania major activates IL-1 alpha expression in macrophages through a MyD88-dependent pathway. Microbes and infection 59 12270723
2018 The role of IL-1 in gout: from bench to bedside. Rheumatology (Oxford, England) 58 29272514
2013 IL-1 and EGF regulate expression of genes important in inflammation and cancer. Cytokine 56 23481102
2005 Central IL-1 receptor signaling regulates bone growth and mass. Proceedings of the National Academy of Sciences of the United States of America 55 16126903
2021 IL-1 family cytokines as drivers and inhibitors of trained immunity. Cytokine 53 34844039
2003 Association of IL1A gene polymorphisms with susceptibility to and severity of systemic sclerosis in the Japanese population. Arthritis and rheumatism 53 12528118
1990 Binding of IL-1 beta to alpha-macroglobulins and release by thioredoxin. Journal of immunology (Baltimore, Md. : 1950) 53 1700994
2014 Association between endometriosis and the interleukin 1A (IL1A) locus. Human reproduction (Oxford, England) 52 25336714
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2017 SAPHO, autophagy, IL-1, FoxO1, and Propionibacterium (Cutibacterium) acnes. Joint bone spine 49 28499891
2003 The IL1A genotype is associated with nasal polyposis in asthmatic adults. Allergy 47 12752325
2016 Inflammasome, IL-1 and inflammation in ozone-induced lung injury. American journal of clinical and experimental immunology 46 27168953
2016 Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement. Molecular neurobiology 46 27356916
1996 Structure-function relationship in the IL-1 family. Frontiers in bioscience : a journal and virtual library 45 9159234
2018 A Guide to IL-1 family cytokines in adjuvanticity. The FEBS journal 44 29656546
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2013 Risk of ovarian cancer and the NF-κB pathway: genetic association with IL1A and TNFSF10. Cancer research 44 24272484
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2017 Cytokines of the IL-1 family: recognized targets in chronic inflammation underrated in organ transplantations. Clinical science (London, England : 1979) 41 28798075
2017 Immunotherapeutic approaches of IL-1 neutralization in the tumor microenvironment. Journal of leukocyte biology 40 28522598
1998 Treatment of rheumatoid arthritis with IL-1 inhibitors. Springer seminars in immunopathology 40 9836379
2021 Role for IL-1 Family Cytokines in Fungal Infections. Frontiers in microbiology 39 33643264
2012 Association between the IL-1 family gene cluster and spondyloarthritis. Annals of the rheumatic diseases 39 22312160
2007 Contribution of single nucleotide polymorphisms of the IL1A gene to the cleavage of precursor IL-1alpha and its transcription activity. Immunogenetics 39 17440718
2011 IL-1 receptor regulates S100A8/A9-dependent keratinocyte resistance to bacterial invasion. Mucosal immunology 38 22031183
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2018 Potential roles of IL-1 subfamily members in glycolysis in disease. Cytokine & growth factor reviews 35 30470512
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