Affinage

IL33

Interleukin-33 · UniProt O95760

Round 2 corrected
Length
270 aa
Mass
30.8 kDa
Annotated
2026-04-28
130 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL-33 is a dual-function alarmin cytokine that operates both as a chromatin-associated nuclear factor and as an extracellular ligand for the ST2/IL-1RAcP receptor complex, orchestrating type 2 immunity, tissue homeostasis, and damage responses across epithelial, endothelial, and immune compartments. Full-length IL-33 is constitutively stored in the nucleus of endothelial and epithelial cells, tethered to chromatin via an N-terminal homeodomain-like HTH motif; upon tissue damage it is released—often as a high-molecular-weight histone complex—and signals through ST2 to activate NF-κB and MAPK cascades that drive TH2, ILC2, mast cell, and eosinophil effector programs (PMID:16286016, PMID:17185418, PMID:18836528, PMID:30108214). Bioactivity is tightly regulated by post-translational processing: neutrophil elastase and cathepsin G generate hyperactive mature forms (~10-fold more potent), thrombin cleaves at R48/R106 to produce additional active species, apoptotic caspases-3/7 inactivate IL-33, and oxidation converts it to a non-ST2-binding form (IL-33ox) that instead engages a RAGE/EGFR pathway driving epithelial remodeling (PMID:22307629, PMID:19559631, PMID:34995358, PMID:37442582). Beyond its extracellular cytokine role, cell-intrinsic nuclear IL-33 maintains regulatory T cell suppressive identity by restraining NF-κB–T-bet–driven IFN-γ epigenetic reprogramming and regulates early B cell development through ST2-independent mechanisms (PMID:31844326, PMID:31391233).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2005 High

    Identification of IL-33 as the functional ligand for the orphan receptor ST2 established that the IL-1 family includes a potent TH2-polarizing cytokine, resolving a long-standing gap in ST2 biology.

    Evidence Receptor-ligand binding assays, NF-κB reporter assays, and in vivo cytokine measurement in mice

    PMID:16286016

    Open questions at the time
    • Mechanism of IL-33 release from cells was unknown
    • Whether IL-33 required processing for activity was unresolved
    • Structural basis of IL-33–ST2 interaction not determined
  2. 2006 High

    Discovery that IL-33 is a chromatin-associated nuclear factor (NF-HEV) with transcriptional repressor activity revealed its dual identity as both an intracellular regulator and an extracellular cytokine.

    Evidence Immunostaining, live-cell imaging of chromatin co-localization, and transcriptional repressor assays

    PMID:17185418

    Open questions at the time
    • Nuclear targets of IL-33 repression were uncharacterized
    • Whether chromatin binding regulates IL-33 release was unknown
  3. 2007 High

    Identification of IL-1RAcP as an obligate co-receptor for ST2 and of soluble ST2 as a decoy receptor defined the complete receptor architecture and a natural brake on IL-33 signaling.

    Evidence Co-immunoprecipitation, dominant-negative IL-1RAcP, direct sST2–IL-33 binding assays, and in vivo functional models

    PMID:17623648 PMID:17675517

    Open questions at the time
    • Stoichiometry of the ternary signaling complex was not resolved
    • Mechanisms governing sST2 shedding were not defined
  4. 2008 High

    Tissue-level surveys established endothelial and epithelial cells as constitutive nuclear reservoirs of IL-33, and functional studies showed IL-33 directly activates eosinophils and mast cells via ST2, defining the key cellular effectors of the pathway.

    Evidence Human tissue microarray immunohistochemistry; primary eosinophil functional assays with ST2 blockade; primary mast cell cytokine and maturation assays

    PMID:17675461 PMID:18539196 PMID:18836528

    Open questions at the time
    • Release mechanism from intact cells was still undefined
    • Relative contributions of mast cells vs. eosinophils in vivo unclear
  5. 2009 High

    Reconstitution of caspase cleavage resolved the critical question of how apoptosis silences IL-33: caspases-3/7 inactivate full-length IL-33 rather than activating it, distinguishing IL-33 from IL-1β/IL-18 and establishing apoptosis as an anti-inflammatory checkpoint for this alarmin.

    Evidence In vitro caspase cleavage with mass spectrometry site mapping, ST2 binding assays, and in vivo bioactivity models

    PMID:19439663 PMID:19559631

    Open questions at the time
    • Whether other proteases generate active forms was unknown
    • In vivo relevance of caspase-mediated inactivation during infection not tested
  6. 2009 High

    Downstream effector biology was elaborated: IL-33 amplifies alternative macrophage activation via IL-13/ST2L crosstalk, drives eosinophil-dependent cutaneous fibrosis through IL-13, and directly induces mast cell cytokine production, establishing IL-33 as a master upstream regulator of type 2 tissue inflammation.

    Evidence Macrophage polarization with ST2-KO mice; ΔdblGATA eosinophil-deficient and IL-13-KO mice; bone marrow eosinophil stimulation assays

    PMID:19841166 PMID:20042577

    Open questions at the time
    • Whether IL-33 drives fibrosis independently of eosinophils in other tissues was unknown
    • Direct transcriptional targets in macrophages were not mapped
  7. 2012 High

    Discovery that neutrophil serine proteases cathepsin G and elastase generate hyperactive (~10-fold more potent) mature IL-33 forms answered how full-length IL-33 is activated in inflammatory microenvironments without inflammasome processing.

    Evidence In vitro protease cleavage with mass spectrometry site identification, neutrophil ex vivo processing, and in vivo bronchoalveolar lavage

    PMID:22307629

    Open questions at the time
    • Whether mast cell proteases similarly process IL-33 was untested
    • Relative contribution of each mature form in disease settings was unclear
  8. 2016 High

    IL-33/ST2 signaling was shown to license thermogenic gene expression (correct Ucp1 splicing) in perinatal adipocytes, extending IL-33 biology beyond immunity into metabolic physiology.

    Evidence IL-33-KO and ST2-KO mice with Ucp1 splicing analysis, UCP1 protein quantification, and thermoregulation phenotyping

    PMID:27453471

    Open questions at the time
    • Mechanism by which IL-33 regulates Ucp1 splicing was not identified
    • Source of IL-33 in the adipose niche was not defined
  9. 2017 Medium

    Nuclear IL-33 was found to form a complex with FAK and chromatin modifiers TAF9, WDR82, and BRD4, driving NF-κB-dependent CCL5 transcription in squamous cell carcinoma, revealing a direct transcriptional co-regulatory function and linking nuclear IL-33 to immune evasion.

    Evidence Nuclear Co-IP of FAK–IL-33 complex, ChIP at target promoters, RNA-seq, shRNA knockdown, syngeneic tumor models

    PMID:29208683

    Open questions at the time
    • Whether the FAK–IL-33 nuclear complex exists outside squamous carcinoma contexts is untested
    • Direct DNA-binding contribution of IL-33 versus scaffolding role not distinguished
    • Awaits independent replication
  10. 2017 High

    A rare loss-of-function splice variant (rs146597587-C) truncating the C-terminal IL-1-like domain confirmed that this domain is absolutely required for ST2 binding, providing human genetic validation of the structure–function relationship.

    Evidence Whole-genome sequencing, allele-specific RNA-seq, recombinant truncated IL-33 binding and activation assays

    PMID:28273074

    Open questions at the time
    • Structural basis of C-terminal domain–ST2 interaction at atomic resolution not resolved
    • Phenotypic consequence in carriers not fully characterized
  11. 2018 High

    FRAP and biochemical fractionation demonstrated that chromatin tethering slows IL-33 release kinetics during necrosis and that IL-33 exits as a histone-bound complex that synergistically enhances ST2 signaling, integrating the nuclear and alarmin functions into a unified release-and-signal mechanism.

    Evidence FRAP live imaging, necrosis-induced release kinetics, size-exclusion chromatography, ST2 reporter assays

    PMID:30108214

    Open questions at the time
    • Identity of the histone partners in the complex not determined
    • Whether histone association affects half-life in vivo was untested
  12. 2018 High

    Discovery that oxidized IL-33 (IL-33ox) loses ST2-binding capacity but gains the ability to signal through a RAGE/EGFR complex revealed a second, ST2-independent signaling axis with distinct pathological consequences in airway epithelial remodeling.

    Evidence Co-IP of IL-33ox–RAGE–EGFR, air-liquid interface epithelial models, single-cell RNA-seq, antibody reversal

    PMID:37442582

    Open questions at the time
    • Structural basis of IL-33ox selectivity for RAGE/EGFR over ST2 unknown
    • Relative abundance of IL-33ox vs. reduced IL-33 in disease tissues not quantified
  13. 2019 High

    Conditional knockout studies revealed that cell-intrinsic nuclear IL-33 maintains Treg suppressive function by preventing NF-κB–T-bet-driven epigenetic reprogramming at the Ifng locus, establishing a major ST2-independent intracellular role in immune homeostasis.

    Evidence Conditional IL-33 KO in Tregs, ATAC-seq of chromatin accessibility, intracellular cytokine flow cytometry, in vivo tumor suppression, T-bet/NF-κB epistasis

    PMID:31844326

    Open questions at the time
    • Molecular mechanism by which nuclear IL-33 restrains T-bet/NF-κB access is not defined
    • Whether this applies to human Tregs is untested
  14. 2019 Medium

    Cell-intrinsic IL-33 was shown to regulate early B cell development in a ST2-independent manner, with IL-33 deficiency increasing E2F/cell cycle programs and expanding developing B cell populations, broadening the nuclear functions beyond Treg biology.

    Evidence Mixed bone marrow chimeras, RNA-seq of WT vs. IL-33−/− pro-B cells, ST2 expression analysis

    PMID:31391233

    Open questions at the time
    • Direct chromatin targets of IL-33 in B cell precursors not identified
    • Protein-level mechanism (scaffolding vs. transcriptional) unclear
    • Single-lab finding
  15. 2019 Medium

    Perforin-2 was identified as a conduit for IL-33 export from dendritic cells, providing a non-necrotic secretory mechanism and linking IL-33 release to regulated mucosal Treg expansion.

    Evidence Conditional IL-33 and perforin-2 KO in CD11c+ cells, flow cytometry of Treg subsets, ex vivo DC stimulation

    PMID:33188058

    Open questions at the time
    • Whether perforin-2 is the sole non-lytic export route is unknown
    • Structural basis of IL-33–perforin-2 interaction not determined
    • Single-lab finding
  16. 2021 High

    Asthma-associated SNP rs1888909 was shown to alter OCT-1 binding at an IL33 enhancer element, providing a mechanistic basis for genetic regulation of IL-33 expression and disease risk.

    Evidence Chromatin conformation capture (3C), enhancer-blocking assays, allele-specific expression, OCT-1 EMSA

    PMID:34675193

    Open questions at the time
    • Full repertoire of transcription factors regulated by this enhancer not mapped
    • Whether additional GWAS SNPs operate through the same element is unknown
  17. 2022 Medium

    Thrombin was identified as a novel activating protease for IL-33 (cleaving at R48 and R106), adding the coagulation cascade to the regulatory protease network and showing that anticoagulants can restrain type 2 immunity by blocking IL-33 maturation.

    Evidence In vitro cleavage with site-directed mutagenesis, multiple in vivo airway inflammation models with thrombin inhibitors

    PMID:34995358

    Open questions at the time
    • Relative potency of thrombin-generated forms vs. neutrophil protease-generated forms not compared
    • In vivo evidence of thrombin-dependent IL-33 cleavage at steady state lacking
  18. 2022 High

    IL-33 in microglia was shown to drive an AP-1/FOS transcriptional program including MARCO upregulation that promotes synapse engulfment, connecting IL-33 to CNS synaptic refinement and seizure susceptibility.

    Evidence ATAC-seq/ChIP of microglial enhancers, CNS-specific IL-33 KO and Marco-KO mice, synapse quantification, EEG seizure monitoring

    PMID:36520518

    Open questions at the time
    • Whether astrocyte- or neuron-derived IL-33 differentially contributes is untested
    • Temporal window of IL-33-dependent synaptic pruning not defined
  19. 2023 Medium

    MDM2-mediated polyubiquitination of the IL-33 N-terminus was identified as a degradation pathway regulated by vitamin B6 (PLP), establishing a metabolic checkpoint for IL-33 protein stability and type 2 inflammation.

    Evidence Ubiquitination assays, proteasome inhibitor rescue, PDXK heterozygous mouse model with elevated lung IL-33

    PMID:37217797

    Open questions at the time
    • Specific ubiquitinated lysine residues not mapped
    • Whether MDM2 regulation is relevant in non-pulmonary tissues untested
    • Single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic-resolution structure of the IL-33–ST2–IL-1RAcP ternary complex, the precise molecular mechanism by which nuclear IL-33 restrains T-bet/NF-κB chromatin remodeling in Tregs, the full spectrum of non-lytic secretion pathways beyond perforin-2, and whether IL-33ox/RAGE/EGFR signaling is a general tissue damage pathway or restricted to airway epithelium.
  • Atomic structure of signaling complex not solved
  • Nuclear mechanism of Treg stabilization molecularly undefined
  • Non-lytic secretion pathway incompletely characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005576 extracellular region 4 GO:0005634 nucleus 4 GO:0005694 chromosome 2
Pathway
R-HSA-168256 Immune System 7 R-HSA-162582 Signal Transduction 6 R-HSA-392499 Metabolism of proteins 5 R-HSA-1643685 Disease 3
Partners
AGERBRD4EGFRIL1RAPIL1RL1PTK2TAF9WDR82
Complex memberships
FAK–IL-33–TAF9–WDR82–BRD4 nuclear complexIL-33ox–RAGE–EGFR complexIL-33–histone release complexST2/IL-1RAcP receptor complex (extracellular ligand)

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 IL-33 was identified as the functional ligand for the orphan IL-1 receptor ST2; binding activates NF-κB and MAP kinases and drives production of TH2-associated cytokines (IL-4, IL-5, IL-13) in vitro and in vivo. Receptor-ligand binding assays, NF-κB reporter assays, in vivo cytokine measurement in mice Immunity High 16286016
2006 IL-33 is a chromatin-associated nuclear factor (identical to NF-HEV) with transcriptional repressor properties; nuclear localization and heterochromatin association are mediated by an evolutionarily conserved homeodomain-like helix-turn-helix (HTH) motif in the N-terminal domain. Immunostaining with multiple antisera, live-cell imaging, co-localization with mitotic chromatin, transcriptional repressor assays Proceedings of the National Academy of Sciences of the United States of America High 17185418
2007 IL-1 receptor accessory protein (IL-1RAcP) forms a co-receptor complex with ST2 to mediate IL-33 signal transduction; IL-1RAcP is required for IL-33-induced in vivo effects and dominant-negative IL-1RAcP blocks IL-33 signaling. Co-immunoprecipitation, dominant-negative constructs, in vivo functional assays Journal of immunology (Baltimore, Md. : 1950) High 17675517
2007 Soluble ST2 (sST2) directly binds IL-33 in the fluid phase, preventing it from interacting with membrane-bound ST2L and thereby suppressing NF-κB activation and Th2 cytokine production. Direct binding assay (soluble ST2–IL-33 interaction), NF-κB reporter assay in ST2L-expressing EL-4 cells, murine asthma model The Journal of biological chemistry High 17623648
2008 IL-33 is constitutively and abundantly expressed in the nucleus of endothelial cells and epithelial cells in normal human tissues in vivo, establishing these cells as major sources and suggesting a dual role as an intracellular nuclear factor and extracellular alarmin. Human tissue microarrays, immunohistochemistry with monoclonal and polyclonal antibodies PloS one High 18836528
2009 Full-length IL-33(1-270) is biologically active and directly binds/activates ST2; caspase-1 cleaves IL-33 after Asp178 (not at Ser111 as previously proposed), resulting in IL-33 inactivation rather than activation. IL-33 is also a substrate for apoptotic caspase-3 at the same consensus motif (DGVD178G). In vitro caspase cleavage assays, ST2 binding assays, site determination by mass spectrometry, cellular activity assays Proceedings of the National Academy of Sciences of the United States of America High 19439663
2009 Apoptotic caspases-3 and -7 (but not inflammatory caspases-1, -4, or -5) process IL-33, and this cleavage dramatically attenuates IL-33 bioactivity both in vitro and in vivo; caspase-dependent proteolysis acts as a switch to dampen IL-33's proinflammatory properties during apoptosis. In vitro caspase activity assays, ST2 binding assays, in vivo bioactivity models, caspase specificity panels Immunity High 19559631
2012 Neutrophil serine proteases cathepsin G and elastase cleave full-length human IL-33(1-270) to generate mature bioactive forms IL-33(95-270), IL-33(99-270), and IL-33(109-270) with ~10-fold higher biological activity than full-length IL-33; these forms are produced by activated human neutrophils ex vivo and are active in vivo. In vitro protease cleavage, mass spectrometry cleavage-site mapping, neutrophil ex vivo assays, in vivo bronchoalveolar lavage model Proceedings of the National Academy of Sciences of the United States of America High 22307629
2009 IL-33 amplifies IL-13-induced polarization of alveolar and bone marrow-derived macrophages toward the alternatively activated (AAM) phenotype via ST2L; IL-13/IL-4Rα signaling is required for this effect by upregulating ST2L expression. AAM-derived CCL24 mediates downstream eosinophil recruitment. In vitro macrophage polarization assays, alveolar macrophage depletion, ST2-knockout mice, cytokine neutralization Journal of immunology (Baltimore, Md. : 1950) High 19841166
2009 IL-33 directly activates primary human mast cells to produce proinflammatory cytokines/chemokines via ST2L, and also accelerates in vitro maturation of CD34+ mast cell precursors. Primary human mast cell culture, cytokine ELISA, CD34+ precursor differentiation assay Journal of immunology (Baltimore, Md. : 1950) High 17675461
2008 Human eosinophils express ST2 (mRNA and protein), and IL-33 stimulates eosinophil superoxide anion production, degranulation, survival, and IL-8 production as potently as IL-5; anti-ST2 antibody blocks these effects. RT-PCR, flow cytometry, superoxide assay, degranulation assay, ELISA, antibody blockade The Journal of allergy and clinical immunology High 18539196
2016 IL-33/ST2 signaling is required for thermogenic licensing of brown and beige adipocytes during the perinatal period; in the absence of IL-33 or ST2, adipocytes fail to express correctly spliced Ucp1 mRNA and UCP1 protein, resulting in impaired uncoupled respiration and thermoregulation, despite normal adipocyte development. IL-33-KO and ST2-KO mice, RNA splicing analysis, UCP1 Western blot, metabolic/thermoregulation phenotyping Cell High 27453471
2018 Nuclear IL-33 binds chromatin with ~10-fold lower intranuclear mobility than IL-1α (measured by FRAP); chromatin binding restrains necrosis-induced IL-33 release (slower, linear kinetics compared to truncated IL-33 or IL-1α) and IL-33 is released as a high-molecular-weight complex with histones that synergistically activates ST2-mediated signaling. FRAP live imaging, necrosis-induced release assays, size-exclusion fractionation, ST2-signaling reporter assays Nature communications High 30108214
2009 IL-33 induces cutaneous fibrosis in an IL-33R (ST2)-dependent manner, requiring IL-13 production and eosinophils; bone marrow-derived eosinophils secrete IL-13 in response to IL-33 stimulation, identifying eosinophil-derived IL-13 as a downstream mediator of IL-33-induced fibrosis. Subcutaneous IL-33 administration, IL-13 knockout mice, ΔdblGATA eosinophil-deficient mice, bone marrow-derived eosinophil stimulation assays Journal of immunology (Baltimore, Md. : 1950) High 20042577
2017 Nuclear FAK enhances IL-33 gene expression in squamous cell carcinoma cells; IL-33 associates with FAK in the nucleus and the FAK-IL-33 complex interacts with chromatin modifiers TAF9, WDR82, and BRD4 to promote NF-κB-driven CCL5 expression and immune evasion. Co-immunoprecipitation (nuclear FAK–IL-33 complex), ChIP, RNA-seq, shRNA knockdown, syngeneic tumor implantation Science signaling Medium 29208683
2021 FAK controls IL-33 gene expression by regulating chromatin accessibility at c-Jun/AP-1 motifs in the Il33 promoter/enhancer region; c-Jun binds the Il33 enhancer in a FAK kinase activity-dependent manner. ATAC-seq, RNA-seq, ChIP for c-Jun, FAK inhibition/overexpression Scientific reports Medium 33420223
2017 IL-33 promotes colon cancer cell stemness through ST2-dependent activation of JNK/c-Jun signaling, which drives binding of c-Jun to promoters of core stem cell genes NANOG, NOTCH3, and OCT3/4; IL-33 also recruits macrophages to produce prostaglandin E2, further supporting stemness. ChIP (c-Jun at stem cell gene promoters), phospho-JNK assays, ST2 pathway inhibition, in vivo tumor models Cancer research Medium 28249897
2010 IL-33 reduces macrophage foam cell formation via the ST2 receptor by decreasing modified LDL uptake (downregulating CD36), reducing cholesterol esterification (downregulating ACAT1), and enhancing cholesterol efflux (upregulating ApoE); ST2-deficient bone marrow-derived macrophages confirm ST2 is required. In vivo ApoE-/- atherosclerosis model, THP-1 and primary human macrophage foam cell assays, cholesterol efflux assays, gene expression, ST2-/- bone marrow-derived macrophages Journal of immunology (Baltimore, Md. : 1950) High 20543107
2017 IL-33 activates SOCS3 expression to inhibit the IL-17 receptor signaling pathway, thereby reducing proinflammatory cytokine production in sepsis; IL-33 KO mice show increased mortality in cecal ligation-puncture sepsis, and this phenotype is linked to unrestrained IL-17 signaling from γδT cells. IL-33-/- mouse CLP model, in vivo cytokine measurement, in vitro MEF knockdown of SOCS3, IL-17 pathway phosphoprotein assays Cellular physiology and biochemistry Medium 28793286
2019 Cell-intrinsic IL-33 (ST2-independent) in regulatory T cells maintains their suppressive function; IL-33-deficient Tregs show NF-κB–T-bet-dependent epigenetic reprogramming (increased chromatin accessibility at the Ifng locus) leading to elevated IFN-γ production that impairs Treg suppressive capacity. Conditional IL-33 KO in Tregs, ATAC-seq, intracellular IFN-γ flow cytometry, in vivo tumor suppression assays, T-bet/NF-κB epistasis Nature immunology High 31844326
2019 IL-33 expressed in dendritic cells (CD11c+ cells) promotes perforin-2 expression on DCs; perforin-2 acts as a plasma membrane conduit for IL-33 export from DCs, facilitating IL-33-driven expansion of ST2+Foxp3+GATA3+ Treg cells and mucosal immunoregulation. Conditional IL-33 KO in CD11c+ cells, conditional perforin-2 KO, flow cytometry of Treg subsets, ex vivo DC stimulation assays Science immunology Medium 33188058
2019 Cell-intrinsic IL-33 (ST2-independent) in pro-B and large precursor B cells regulates early B cell development; IL-33 deficiency leads to increased E2F targets/cell cycle genes and decreased p53 pathway activity, resulting in increased frequency of developing B cells via a cell-intrinsic mechanism. Mixed bone marrow chimeric mice, RNA-seq of WT vs IL-33-/- pro-B cells, ST2 expression analysis by RT-PCR and flow cytometry Journal of immunology (Baltimore, Md. : 1950) Medium 31391233
2021 IL-33 activates mTORC1 in CD8+ T cells (evidenced by increased phospho-S6), and this mTORC1 activation drives upregulation of Glut1 and glycolytic enzymes, leading to increased glycolytic capacity (Warburg effect) and enhanced CD8+ T cell effector activation. Adoptive transfer experiments, phospho-S6 Western blot/flow cytometry, mTORC1 inhibitor rescue, glycolytic rate assay, Glut1 expression analysis Immunology Medium 34411293
2022 Thrombin directly cleaves IL-33 at specific amino acids R48 and R106 to generate a mature bioactive form; low-molecular-weight heparin (thrombin inhibitor) restrains type 2 immune responses in mice by inhibiting IL-33 cleavage. In vitro protease cleavage with site-directed mutagenesis, in vivo papain/fungus/HDM/OVA airway inflammation models with thrombin inhibitors Allergy Medium 34995358
2021 IL-33 precedes IL-5 in regulating eosinophil commitment; IL-33 (via ST2) supports eosinophil maturation by driving systemic IL-5 production AND by expanding IL-5Rα-expressing precursor cells in bone marrow, establishing a two-step mechanism for eosinophilopoiesis. IL-33-KO and ST2-KO mice, IL-5 neutralization, in vitro bone marrow culture with IL-33/IL-5, IL-5 transgenic × ST2-KO crosses Journal of immunology (Baltimore, Md. : 1950) High 27683753
2021 GSK3β inhibition downstream of PI3K/Akt (induced by IL11 via STAT3) promotes epithelial IL-33 expression; IL11 is the most potent known inducer of IL33 in fibroblasts (38-fold upregulation), and STAT3 inhibition (but not MEK/ERK inhibition) prevents this induction. RNA-seq time course, STAT3 and MEK inhibitors, IL-33 protein quantification in primary human fibroblasts from kidney, lung, and skin International journal of molecular sciences Medium 36012165
2018 Oxidized IL-33 (IL-33ox, non-ST2-binding form) forms a complex with RAGE and EGFR on airway epithelium, activating an ST2-independent pathway that impairs wound closure, increases mucus-producing cells, and induces epithelial remodeling mimicking COPD pathology. Co-immunoprecipitation of IL-33ox–RAGE–EGFR complex, in vitro epithelial damage assays, air-liquid interface models, single-cell RNA-seq, IL-33-neutralizing antibody reversal The European respiratory journal High 37442582
2023 PLP (active vitamin B6) regulates IL-33 protein stability by reducing MDM2-mediated polyubiquitination of the IL-33 N-terminus, leading to increased proteasomal degradation of IL-33 and attenuation of type 2 inflammation; PDXK heterozygous mice (reduced PL→PLP conversion) show elevated lung IL-33 and worsened type 2 inflammation. In vivo PDXK heterozygous and MDM2 knockdown mouse models, ubiquitination assays, proteasome inhibitor rescue, IL-33 stability measurements Cellular & molecular immunology Medium 37217797
2019 IL-33 inactivates GSK-3β through an ST2-independent MyD88/TRAF6/RIP/PI3K/Akt signaling pathway in PC-12 cells, and neutralizes Aβ1-42-induced Akt inactivation and GSK-3β activation. siRNA knockdown of MyD88, TRAF6, RIP, PI3K; Western blot for Akt and GSK-3β phosphorylation Heliyon Medium 30533546
2021 Asthma-associated SNP rs1888909 within a 5 kb enhancer-blocking element at the IL33 locus alters binding of the transcription factor OCT-1 (POU2F1) in an allele-specific manner, regulating IL33 gene expression in airway epithelial cells and IL-33 protein levels in plasma. Chromatin conformation capture (3C), in vivo and in vitro enhancer-blocking assays, allele-specific expression analysis (RNA-seq), OCT-1 binding EMSA Nature communications High 34675193
2017 A rare splice-acceptor variant in IL33 (rs146597587-C) causes intron retention with a premature stop codon, truncating the last 66 amino acids; the truncated IL-33 protein has normal intracellular localization but neither binds ST2 nor activates ST2-expressing cells, confirming the C-terminal IL-1-like domain is essential for receptor binding and activity. Whole-genome sequencing, allele-specific RNA-seq, recombinant truncated IL-33 binding and cell activation assays, cellular localization imaging PLoS genetics High 28273074
2019 IL-33 reduces CLDN1 (claudin-1) expression in keratinocytes through the ERK/STAT3 pathway; STAT3 directly binds the CLDN1 promoter to suppress transcription, leading to impaired skin barrier function. MAPK inhibitors, siRNA knockdown, EMSA/EMSA (STAT3 binding to CLDN1 promoter), TEER and FITC-dextran flux assays Journal of dermatological science Medium 29534857
2022 P2Y13 receptor (a purinergic GPCR) acts as a gatekeeper of IL-33 release from airway epithelial cells; aeroallergen or virus exposure triggers extracellular ADP/ATP release that activates P2Y13-R, inducing nuclear-to-cytoplasmic translocation and subsequent secretion of IL-33; genetic deletion or pharmacological antagonism of P2Y13 ablates this response. P2Y13-R knockout mice, pharmacological antagonism, immunohistochemistry for nuclear-to-cytoplasmic translocation, ELISA, experimental asthma models American journal of respiratory and critical care medicine Medium 34860143
2019 Glutaredoxin-1 (Glrx) controls NF-κB-dependent IL-33 induction in macrophages by maintaining TRAF6 in its de-glutathionylated (active) state; Glrx knockdown impairs TRAF6 de-glutathionylation, blocks IKKβ/NF-κB activation, and reduces LPS-induced IL-33 mRNA; paracrine IL-33 in turn induces Glrx, creating a feed-forward loop. Glrx KO mice, siRNA knockdown, S-glutathionylation assay of TRAF6, NF-κB reporter, chromatin IP confirming NF-κB binding to Il33 locus PloS one Medium 30682073
2022 IL-33 signaling in microglia promotes synaptic refinement by inducing an AP-1/FOS-driven gene expression program including the scavenger receptor MARCO; MARCO promotes synapse engulfment and CNS-specific IL-33 deletion causes excess excitatory synapses and seizure susceptibility. IL-33 supraphysiological CNS delivery, microglial enhancer landscape (ATAC-seq/ChIP), CNS-specific IL-33 KO mice, Marco-KO mice, synapse counting, EEG seizure monitoring The Journal of experimental medicine High 36520518
2020 Staphylococcus aureus second immunoglobulin-binding protein (Sbi) is the predominant virulence factor that drives rapid release of constitutively stored IL-33 from human keratinocytes, independently of Toll-like receptor signaling and independently of necrosis; this IL-33 release is essential for the type 2 immune response to S. aureus in vivo. FPLC fractionation, mass spectrometry, S. aureus Sbi mutant strains, recombinant Sbi expression, in vivo NC/Tnd mouse model with IL-33 blockade The Journal of allergy and clinical immunology High 33011245

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 3006 16286016
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2010 A large-scale, consortium-based genomewide association study of asthma. The New England journal of medicine 1582 20860503
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1996 Selective interaction of JNK protein kinase isoforms with transcription factors. The EMBO journal 1119 8654373
2008 The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel 'alarmin'? PloS one 970 18836528
2016 Interleukin-33 in health and disease. Nature reviews. Immunology 920 27640624
2006 IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proceedings of the National Academy of Sciences of the United States of America 822 17185418
2013 A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. The Journal of experimental medicine 791 24323357
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2008 IL-1, IL-18, and IL-33 families of cytokines. Immunological reviews 701 18613828
2018 Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family. Immunological reviews 667 29247993
2011 Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nature genetics 656 21804549
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nature reviews. Drug discovery 648 18827826
2013 TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Science translational medicine 627 23363980
2009 Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nature genetics 622 19198610
2009 IL-33 amplifies the polarization of alternatively activated macrophages that contribute to airway inflammation. Journal of immunology (Baltimore, Md. : 1950) 584 19841166
2009 The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proceedings of the National Academy of Sciences of the United States of America 569 19439663
2009 Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity 559 19559631
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