| 2013 |
Crystal structure of IL-33 in complex with the ectodomain of ST2 determined at 3.27 Å resolution. Structure-based mutagenesis and binding assays defined the molecular mechanism by which ST2 specifically recognizes IL-33, showing surface-charge complementarity is critical for ligand-binding specificity. Small-angle X-ray scattering revealed that ST2 possesses hinge flexibility between its D3 domain and D1D2 module, while IL-1RAcP is rigid in the unbound state. The solution architecture of the IL-33–ST2–IL-1RAcP ternary complex was also determined. |
X-ray crystallography, SAXS, structure-based mutagenesis, binding assay |
Proceedings of the National Academy of Sciences of the United States of America |
High |
23980170
|
| 2018 |
Nuclear IL-33 binds chromatin with ~10-fold slower intranuclear mobility than IL-1α (measured by FRAP). Chromatin binding restricts IL-33 release upon necrosis (full-length IL-33 is more resistant to necrosis-induced release than truncated IL-33 lacking chromatin-binding activity). Upon release, IL-33 and histones form a high-molecular-weight complex that synergistically activates ST2-mediated signaling, indicating chromatin binding is a post-translational mechanism regulating IL-33 releasability and bioactivity. |
FRAP, overexpression in epithelial cells, necrosis-induced release assay, gel filtration/high-MW complex analysis, receptor signaling assay |
Nature communications |
High |
30108214
|
| 2014 |
USP21, a ubiquitin-specific protease, interacts with IL-33 in the nucleus and deubiquitinates it, thereby maintaining IL-33 protein stability. Depletion of USP21 reduces IL-33 protein levels and diminishes IL-33-mediated NF-κB p65 promoter transcriptional activity, linking IL-33 ubiquitination to its nuclear function. |
Co-immunoprecipitation, overexpression/knockdown, proteasome assay, NF-κB reporter assay |
International journal of clinical and experimental pathology |
Medium |
25197364
|
| 2017 |
IL-33 activates core stem cell genes (NANOG, NOTCH3, OCT3/4) in colon cancer cells via the ST2 signaling pathway and induces phosphorylation and activation of JNK; activated c-Jun then binds the promoters of these stem cell genes. IL-33 also recruits macrophages into the tumor microenvironment and stimulates them to produce prostaglandin E2, which further supports cancer stemness. |
In vitro stimulation, Western blotting for p-JNK, chromatin immunoprecipitation (c-Jun on stem cell gene promoters), overexpression/administration in vivo tumor models, macrophage co-culture |
Cancer research |
Medium |
28249897
|
| 2018 |
IL-33 activates dendritic cells via an IL-33–ST2–MyD88–STAT1 signaling axis. MyD88 is required for IL-33-mediated increases in myeloid DC (mDC) number and upregulation of costimulatory molecules; ST2 and STAT1 cooperate with MyD88 to induce costimulatory molecule expression on mDCs in response to IL-33. |
In vivo rIL-33 administration, genetic knockout of MyD88/ST2/STAT1, flow cytometry, antigen cross-presentation assay |
Journal of immunology (Baltimore, Md. : 1950) |
Medium |
28011934
|
| 2018 |
A loss-of-function splice-site mutation in IL33 (rs146597587-C) produces a truncated IL-33 protein that has normal intracellular localization but neither binds the IL-33 receptor ST2 nor activates ST2-expressing cells, demonstrating that the C-terminal region (last 66 amino acids) is required for receptor binding and functional activity. |
Whole-genome sequencing, allele-specific RNA sequencing, recombinant truncated IL-33 protein binding assay, cell activation assay |
PLoS genetics |
High |
28273074
|
| 2019 |
IL-33-deficient Treg cells show attenuated suppressive properties and facilitate tumor regression in an ST2-independent fashion. On activation, Il33-/- Treg cells exhibit epigenetic reprogramming with increased chromatin accessibility at the Ifng locus, leading to elevated IFN-γ production via an NF-κB–T-bet-dependent mechanism. IFN-γ ablation restores Il33-/- Treg cell suppressive properties, establishing IFN-γ as the effector of IL-33-dependent Treg stability. |
Genetic knockout (Il33-/- Tregs), ATAC-seq, in vivo tumor models, IFN-γ ablation rescue experiment |
Nature immunology |
High |
31844326
|
| 2020 |
Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in hippocampal CA1. Neuronal activity blockade increases IL-33 expression and secretion by CA1 astrocytes; this IL-33 stimulates excitatory synapse formation and neurotransmission by activating the neuronal IL-33 receptor complex and promoting synaptic recruitment of PSD-95. Conditional knockout of IL-33 in CA1 astrocytes decreases excitatory synapse number, and blockade of IL-33/ST2 signaling impairs homeostatic plasticity and spatial memory. |
Conditional KO, optogenetic inhibition, tetrodotoxin slice experiments, in vivo rIL-33 administration, intracerebroventricular decoy receptor injection, behavioral memory assays, immunostaining for PSD-95 |
Proceedings of the National Academy of Sciences of the United States of America |
High |
33443211
|
| 2022 |
IL-33 promotes microglial synapse remodeling during brain development. Supraphysiological IL-33 alters the microglial enhancer landscape and increases binding of AP-1/FOS transcription factors, inducing expression of the scavenger receptor MARCO. CNS-specific deletion of IL-33 leads to increased excitatory/inhibitory synaptic balance and absence-like epileptiform activity; MARCO-deficient mice recapitulate excess thalamic excitatory synapses, indicating MARCO as a downstream mediator of IL-33-driven synapse engulfment. |
CNS-specific IL-33 KO mice, ATAC-seq/enhancer landscape analysis, MARCO KO, single-cell electrophysiology, EEG, synapse counting |
The Journal of experimental medicine |
High |
36520518
|
| 2024 |
Oxidized IL-33 (IL-33ox), a non-ST2-binding form, activates an ST2-independent pathway by forming a complex with RAGE and EGFR on airway epithelial cells. Activation of this RAGE/EGFR complex impairs epithelial wound closure and induces airway remodeling (increased mucus-producing cells, reduced epithelial defense functions) in vitro and in COPD ALI cultures. |
In vitro epithelial damage assays, 3D air-liquid interface models, bulk and single-cell RNA sequencing, antibody-based pathway neutralization |
The European respiratory journal |
Medium |
37442582
|
| 2022 |
Thrombin directly cleaves IL-33 at specific amino acid residues (R48 and R106) to generate a mature, biologically active form with potent ST2-stimulating activity. Low-molecular-weight heparin (indirect thrombin inhibitor) restrains papain- and fungus-induced type 2 immune responses by inhibiting IL-33 cleavage in vivo. |
In vitro cleavage assay (identification of cleavage sites R48/R106), in vivo mouse models with thrombin inhibitors, ELISA, ILC2 functional assays |
Allergy |
Medium |
34995358
|
| 2023 |
MDM2 (an E3 ubiquitin ligase) ubiquitinates the N-terminus of IL-33 and sustains its stability in epithelial cells. PLP (active form of vitamin B6) reduces MDM2-mediated IL-33 polyubiquitination and decreases IL-33 levels through the proteasome pathway, thereby dampening type 2 immune responses. |
In vivo PLP/PL administration, Pdxk heterozygous mice, ubiquitination assay, proteasome inhibitor experiments, co-immunoprecipitation |
Cellular & molecular immunology |
Medium |
37217797
|
| 2021 |
Focal adhesion kinase (FAK) controls chromatin accessibility at the Il33 gene promoter/enhancer regions. FAK kinase activity is required for c-Jun (AP-1) binding to the Il33 enhancer, thereby regulating IL-33 gene expression. ATAC-seq integrated with RNA-seq demonstrated FAK-dependent chromatin accessibility linked to Il33 differential expression. |
ATAC-seq, RNA-seq, ChIP (c-Jun binding to Il33 enhancer), pharmacological/genetic FAK manipulation |
Scientific reports |
Medium |
33420223
|
| 2021 |
Sprouty2 loss in colonic epithelial cells activates PI3K/Akt signaling leading to GSK3β inhibition, which in turn drives epithelial IL-33 expression. Elevated epithelial IL-33 increases stromal IL-13+ cells in vivo; IL-13 then induces tuft and goblet cell expansion. This PI3K–Akt–GSK3β–IL-33–IL-13 axis links epithelial signaling to secretory cell differentiation. |
Conditional Sprouty2 KO, in vivo intestinal phenotyping, in vitro organoids with PI3K/Akt inhibitors, GSK3β inhibitor treatment, IL-13 neutralization |
Nature communications |
Medium |
33547321
|
| 2022 |
IL11 stimulation of fibroblasts induces IL-33 expression (38-fold upregulation) in a STAT3-dependent (not MEK/ERK-dependent) manner, as demonstrated by pharmacological inhibition of STAT3 versus MEK/ERK. IL11 also upregulates IL1RL1 (the IL-33 receptor) 18-fold in the same cells, priming the IL-33 alarmin response. |
Primary human fibroblast culture, RNA sequencing, STAT3 and MEK/ERK pharmacological inhibitors, proteomics |
International journal of molecular sciences |
Medium |
36012165
|
| 2019 |
IL-33 activates mTORC1 in CD8+ T cells (evidenced by increased phospho-S6 ribosomal protein), leading to upregulation of Glut1 and glycolytic enzymes via mTORC1, and increased glucose uptake and lactate production (Warburg effect). mTORC1 inhibitors suppressed IL-33-induced CD8+ T cell activation. Extracellular (not nuclear) IL-33 contributed to CD8+ T cell activation in LCMV infection in vivo. |
Adoptive transfer of IL-33 KO vs. WT T cells, in vitro stimulation assays, phospho-S6 Western blot/flow cytometry, mTORC1 inhibitor treatment, glycolytic rate assay, glucose uptake measurement |
Immunology |
Medium |
34411293
|
| 2011 |
IL-33 promotes acute kidney injury (AKI) through CD4+ T cell-mediated production of CXCL1. Administration of soluble ST2 (decoy receptor) reduced CD4+ T cell infiltration, serum creatinine, ATN and apoptosis; conversely, recombinant IL-33 exacerbated AKI, and this exacerbation did not occur in CD4-deficient mice. CXCL1 receptor-deficient mice also showed attenuated AKI, placing the pathway as IL-33 → CD4 T cells → CXCL1 → renal injury. |
Soluble ST2 administration, recombinant IL-33 administration, CD4-deficient mice, CXCL1 receptor KO mice, serum creatinine, histopathology, cytokine ELISA |
Journal of the American Society of Nephrology : JASN |
Medium |
21949094
|
| 2010 |
IL-33 exacerbates autoantibody-induced arthritis specifically through mast cells expressing ST2. Mast cell-deficient mice and ST2-/- mice failed to show IL-33-mediated disease exacerbation; reconstitution of ST2-/- recipients with WT mast cells (but not ST2-/- mast cells) restored IL-33-mediated exacerbation. IL-33 enhanced autoantibody-mediated mast cell degranulation in vitro and in synovial tissue in vivo. |
ST2-/- mice, mast cell-deficient mice, mast cell reconstitution experiments, in vitro mast cell degranulation assay, in vivo synovial tissue analysis |
Journal of immunology (Baltimore, Md. : 1950) |
High |
20139274
|
| 2024 |
Active secretion of IL-33 from astrocytes occurs via an unconventional protein secretion pathway dependent on interaction with TMED10 (transmembrane emp24 domain 10). The IL-1-like cytokine domain of IL-33 mediates this interaction. IFN-γ promotes active secretion. Knockout of Il-33 or its receptor St2 induced hippocampal and spinal cord astrocyte activation and depressive-like behavior in naïve mice. |
Co-immunoprecipitation (IL-33 with TMED10), domain mapping, IL-33/ST2 conditional KO, behavioral assays, EAE model |
Brain, behavior, and immunity |
Medium |
38663774
|
| 2014 |
Epithelial nuclear IL-33 is upstream of IL-8 and IL-6 production in esophageal epithelial cells. IFN-γ induces nuclear IL-33 expression via a JAK/p38 MAPK/STAT1 pathway; IL-33 knockdown (siRNA) dampens IFN-γ- and deoxycholic acid-induced IL-8 and IL-6 production, establishing a non-cytokine, intranuclear regulatory function for IL-33 in esophageal inflammation. |
IL-33 siRNA knockdown, STAT1 siRNA, JAK and p38 MAPK inhibitors, cytokine ELISA, stratified epithelial culture model |
Journal of gastroenterology |
Medium |
25129514
|
| 2021 |
The asthma-associated SNP rs1888909 within an enhancer-blocking element at the IL33 locus is associated with IL33 gene expression in airway epithelial cells and IL-33 protein levels in plasma, potentially through differential binding of the transcription factor OCT-1 (POU2F1) to the risk allele. Chromatin conformation capture showed this 5 kb region loops to the IL33 promoter. |
3C (chromatin conformation capture), reporter assays (enhancer-blocking), eQTL analysis in airway epithelial cells, OCT-1 binding assay |
Nature communications |
Medium |
34675193
|
| 2019 |
Glutaredoxin-1 (Glrx) controls IL-33 production in macrophages by regulating de-glutathionylation of TRAF6, which is required for TRAF6 activation; this in turn activates IKKβ and NF-κB, which drives IL-33 transcription as a NF-κB-responsive gene. Glrx knockdown also impairs downstream IL-33-induced (exogenous, via ST2L) IL-33 mRNA induction. |
Glrx KO mice, siRNA knockdown in RAW264.7 cells, chromatin IP-seq (NF-κB binding at IL-33 promoter), TRAF6 glutathionylation assay, NF-κB inhibitors |
PloS one |
Medium |
30682073
|
| 2018 |
IL-33 expression in Multiple Sclerosis PBMCs is regulated by HDAC3: IL-33 expression is inhibited by the HDAC inhibitor Trichostatin A (TSA), while IL-1β expression is not, indicating specific epigenetic regulation of IL-33 by HDAC activity. LPS stimulation co-induces IL-33 and HDAC3 in RRMS patients. |
HDAC inhibitor (TSA) treatment of PBMCs, LPS stimulation, RT-PCR/protein quantification |
Annals of clinical and translational neurology |
Low |
25215310
|
| 2023 |
P2Y13 receptor (a purinergic GPCR) acts as a gatekeeper of nuclear IL-33 release in airway epithelial cells. Aeroallergen or virus exposure induces extracellular ADP/ATP release, activating P2Y13-R, which drives nuclear-to-cytoplasmic translocation and subsequent extracellular release of IL-33. Genetic deletion or pharmacological antagonism of P2Y13-R ablates IL-33 translocation and release in response to allergens and rhinovirus. |
P2Y13-R knockout mice and pharmacological antagonists, allergen/virus exposure of primary AECs, immunohistochemistry for IL-33 localization, ELISA |
American journal of respiratory and critical care medicine |
Medium |
34860143
|
| 2020 |
S. aureus second immunoglobulin-binding protein (Sbi) directly drives rapid IL-33 release from human keratinocytes independently of the Toll-like receptor pathway. Sbi was identified by FPLC fractionation and mass spectrometry, confirmed by recombinant expression and S. aureus Sbi mutant strains; IL-33 was essential for the in vivo immune response to S. aureus in eczema-prone mice. |
FPLC fractionation, mass spectrometry, recombinant Sbi expression, Sbi mutant bacteria, ex vivo skin explants, IL-33 KO mice |
The Journal of allergy and clinical immunology |
Medium |
33011245
|
| 2024 |
Lenvatinib increases NDUFA4L2 expression in HCC cells, which promotes IL-33 production and secretion. Secreted IL-33 triggers neutrophil extracellular trap (NET) formation by increasing PADI4 expression in neutrophils via the Akt/mTOR signaling pathway. IL-33 knockdown in HCC cells reduced NET formation in the tumor microenvironment. |
IL-33 KO/knockdown in tumor cells, NDUFA4L2 overexpression, mTOR inhibitor (rapamycin), PADI4 inhibitor (GSK484), NET quantification (CitH3, MPO-DNA), in vivo HCC mouse models |
Cellular oncology (Dordrecht, Netherlands) |
Medium |
39585643
|
| 2015 |
IL-33 stimulation induces ICAM-1 expression on murine bone-marrow-derived mast cells at both mRNA and protein levels. This induction is dependent on NF-κB signaling: pre-treatment with an NF-κB inhibitor dramatically reduces ICAM-1 expression. IL-33-treated mast cells show increased cell adhesion to LFA-1-coated surfaces. |
BMMCs stimulation, siRNA knockdown of ICAM-1, NF-κB inhibitor, cell adhesion assay, in vivo intradermal IL-33 injection with histological analysis |
Allergology international : official journal of the Japanese Society of Allergology |
Medium |
26666474
|
| 2018 |
IL-33 facilitates colorectal cancer cell proliferation via ST2 receptor → NF-κB signaling → COX2 upregulation → PGE2 production. ST2 blockade, NF-κB inhibition (shP65), and COX2 selective inhibitor or PGE2 neutralizing antibody each abolished the IL-33 proliferation-promoting effect. ST2-negative sorted primary CRC cells did not respond to IL-33. |
ST2 blocking antibody, flow cytometry sorting of ST2+/- cells, NF-κB shRNA, COX2 inhibitor, PGE2 neutralizing antibody, colony formation and viability assays, in vivo IL-33 transgenic tumor growth |
Journal of experimental & clinical cancer research : CR |
Medium |
30119635
|