| 2007 |
IL-33 is the functional ligand for the transmembrane ST2L receptor; sST2 acts as a soluble decoy receptor that sequesters IL-33 and blocks the antihypertrophic IL-33/ST2L signaling in cardiomyocytes. ST2-knockout mice subjected to pressure overload (transverse aortic constriction) showed more left ventricular hypertrophy, fibrosis, and impaired survival compared to WT, and recombinant IL-33 treatment rescued WT but not ST2-/- mice. |
ST2-knockout mouse model, transverse aortic constriction pressure overload, recombinant IL-33 treatment, cardiomyocyte hypertrophy assays, NF-κB signaling assays, IκBα phosphorylation measurement |
The Journal of clinical investigation |
High |
17492053
|
| 2007 |
IL-33/ST2 signaling is mechanically activated: IL-33 is produced predominantly by cardiac fibroblasts in response to biomechanical strain, and signals to cardiomyocytes (which express ST2L), constituting a fibroblast-cardiomyocyte paracrine cardioprotective system. |
In vitro mechanical stretch of cardiac fibroblasts, immunohistochemistry, cardiomyocyte-fibroblast coculture assays |
The Journal of clinical investigation |
High |
17492053
|
| 2001 |
ST2V, a third splice variant of the ST2/IL1RL1 gene, localizes to the plasma membrane (not secreted like sST2) and is predominantly expressed in the stomach, small intestine, and colon; subcellular fractionation placed it in the insoluble/membrane fraction. |
RT-PCR tissue distribution, COS7 transfection, radiolabeling, subcellular fractionation, confocal laser microscopy, monoclonal antibody detection |
Biochemical and biophysical research communications |
Medium |
11478810
|
| 1997 |
ST2 mRNA and protein expression (both soluble and membrane-anchored isoforms) are induced by pro-inflammatory stimuli (TNF, IL-1α, IL-1β, PMA) in human and murine cells; soluble ST2 expression is inducible while membrane ST2 expression remains constitutive. |
Northern/Western blotting using ST2 cDNA probes and polyclonal antibody, cytokine and PMA treatment of BALB/c-3T3 cells, UVB irradiation mouse model |
Biochemical and biophysical research communications |
Medium |
9207179
|
| 2013 |
The membrane-bound ST2L forms a receptor complex with IL-1 receptor accessory protein (IL-1RAcP/IL1RAP) to transduce IL-33 signaling, activating NF-κB and MAPK pathways. IL1RL1 missense variants in the intracellular (TIR) domain increase sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness via ST2L. |
Cell culture model with IL1RL1 missense variant expression, sST2 quantification, GWAS of Framingham Offspring Cohort (n=2,991), functional characterization of SNP effects on IL-33 signaling |
The Journal of clinical investigation |
Medium |
23999434
|
| 2014 |
IL-33/ST2 axis promotes mast cell survival specifically through the anti-apoptotic molecule BCLXL; ST2-deficient mice had fewer tissue mast cells in inflamed joints, helminth-infected intestine, and normal peritoneum. Peritoneal transfer confirmed a cell-intrinsic ST2 role, with WT mast cells surviving better than ST2-/- mast cells in an IL-33-dependent manner. |
ST2-knockout mouse model, in vitro apoptosis assay with human and murine mast cells, BCLXL inhibition/knockdown, peritoneal mast cell transfer experiments, flow cytometry, IL-33 blockade |
Proceedings of the National Academy of Sciences of the United States of America |
High |
24982172
|
| 2012 |
Soluble mST2 protein inhibits Th2 cytokine production (IL-4 and IL-5 but not IFN-γ) from allergen-stimulated splenocytes in vitro and, when transferred in vivo by gene transfer, reduces eosinophil numbers and IL-4/IL-5 levels in bronchoalveolar lavage fluid in a murine asthma model. |
In vitro splenocyte stimulation assay, in vivo intravenous mST2 gene transfer in OVA-sensitized mice, BAL fluid cytokine/eosinophil quantification |
Clinical and experimental allergy |
Medium |
12372135
|
| 2015 |
ST2 deficiency in T regulatory (Treg) cells does not impair their accumulation in nonlymphoid organs including visceral adipose tissue, but cell-intrinsic ST2 signaling is required for type 2 cytokine production by VAT-resident Tregs and for limiting IL-17A-producing γδT cells in the CNS during neuroinflammation (EAE model). |
Conditional ST2 knockout limited to Treg cells (Foxp3-Cre), EAE neuroinflammation model, flow cytometry, cytokine measurement |
The Journal of experimental medicine |
High |
33095261
|
| 2015 |
ST2 signaling contributes to T-cell hyperactivation and fatal hemophagocytic lymphohistiocytosis (FHL) in mice: ST2 blockade in perforin-deficient LCMV-infected mice markedly improved survival and reduced IFNγ-producing CD8+ and CD4+ T cells, implicating IL-33/ST2 as an amplifier of immune dysregulation via MyD88-dependent signaling. |
ST2 blockade in Prf1-/- LCMV-infected mice, survival analysis, flow cytometry for IFNγ-producing T cells, serum IFNγ measurement |
Blood |
High |
26518437
|
| 2017 |
ST2 receptor is highly expressed on microglia and is upregulated after ischemic stroke (tMCAO). ST2 deficiency shifts microglia/macrophages toward M1 polarization, expands brain infarcts, and exacerbates neurological deficits. IL-33/ST2 signaling stimulates microglial production of IL-10, which is critical for neuroprotection; IL-33 treatment failed to protect IL-10 knockout mice. |
ST2-knockout mice, tMCAO and permanent MCAO stroke models, intracerebroventricular IL-33 infusion, flow cytometry, in vitro microglial cultures and coculture systems, IL-10 KO mice |
The Journal of neuroscience |
High |
28389473
|
| 2020 |
TGF-β signaling upregulates IL1RL1 (ST2) expression in ILC2 progenitors and common helper-like innate lymphoid progenitors (CHILP) at least partially through the MEK-dependent pathway, and is required for efficient ILC2 development from progenitors. |
TGF-β receptor II conditional knockout in bone marrow progenitors, flow cytometry of ILC2 progenitors, MEK inhibition experiments, IL1RL1 mRNA expression measurement |
Nature communications |
Medium |
31911623
|
| 2020 |
Helminth-derived protein HpBARI binds murine ST2 directly, inhibits cell-surface detection of ST2, prevents IL-33-ST2 interactions, and blocks IL-33 responses in vitro and in vivo. HpBARI_Hom2 binds human ST2 with high affinity and effectively blocks human PBMC responses to IL-33. |
Protein binding assays, cell-surface ST2 detection, in vitro IL-33 stimulation assays, in vivo mouse model of asthma, human PBMC IL-33 response assays |
eLife |
High |
32420871
|
| 2016 |
IL1RL1 risk SNPs rs1420101 and rs11685480 act as expression QTLs in airway epithelial cells and distal lung parenchyma respectively (not in whole blood), regulating sST2 production from the lung; the genetically determined plasma sST2 reservoir neutralizes IL-33 activity and these eQTL SNPs additively increase risk of airway type 2 inflammation among asthmatics. |
eQTL analysis in airway epithelial cells and lung parenchyma, plasma sST2 measurement, IL-33 neutralization assay, genetic association analysis in asthmatic cohorts |
JCI insight |
Medium |
27699235
|
| 2020 |
IL1RL1 TIR signaling domain haplotype SNPs affect IL-33-driven NF-κB signaling in bronchial epithelial cells without interfering with TLR signaling, providing mechanistic insight into how coding variants alter receptor signaling. |
Primary bronchial epithelial cell cultures with IL-33 stimulation, NF-κB reporter assays, TLR signaling assays, haplotype analysis |
JCI insight |
Medium |
32324168
|
| 2012 |
PU.1, an Ets-family transcription factor, directly transactivates the human ST2/IL1RL1 promoter via an Ets-family binding cis-element in mast cells (LAD2) and basophils (KU812); siRNA-mediated knockdown of PU.1 significantly reduced ST2 mRNA levels. |
Reporter assay with wild-type and mutant ST2 promoter constructs, EMSA to identify PU.1 binding, siRNA knockdown of PU.1 with ST2 mRNA quantification |
Allergology international |
Medium |
22824976
|
| 2018 |
Lungs are a major source of soluble ST2 (sST2) in heart failure; in an experimental ischemic heart failure model, sST2 increased significantly in lungs from week 1, and primary human type II pneumocytes secrete sST2 in response to mechanical strain. Lung aspirate sST2 levels were dramatically higher in cardiogenic pulmonary edema versus other conditions. |
Experimental ischemic heart failure model with time-course mRNA/protein quantification, primary human type II pneumocyte strain cultures, sST2 measurement in bronchial aspirates, immunostaining of alveolar epithelium |
Circulation. Heart failure |
Medium |
30562096
|
| 2020 |
sST2 induces human cardiac fibroblast activation and collagen synthesis via upregulation of neuropilin-1 (NRP-1), a regulator of profibrotic TGF-β1. NF-κB inhibition restored NRP-1 levels and blocked sST2 profibrotic effects; NRP-1 knockdown abolished sST2-induced fibroblast activation and collagen synthesis. |
Proteomics of human cardiac fibroblasts treated with sST2, NF-κB pharmacological inhibition, NRP-1 siRNA knockdown, exogenous NRP-1 overexpression, pressure overload rat model with sST2/NRP-1 correlation |
Cells |
High |
32664340
|
| 2023 |
Oxidised IL-33 (IL-33ox, which does not bind ST2) forms a functional complex with RAGE and EGFR on airway epithelium, activating an ST2-independent pathway that impairs epithelial wound closure and induces airway remodelling (increased mucus-producing cells, reduced epithelial defence) mimicking COPD pathology. |
In vitro epithelial damage assays, 3D air-liquid interface cultures (healthy and COPD), transcriptomics (bulk and single-cell RNA-seq), IL-33-neutralising antibody treatment, co-immunoprecipitation/complex formation of RAGE-EGFR |
The European respiratory journal |
High |
37442582
|
| 2023 |
IL1RL1 signaling in Treg cells promotes immunosuppression in the tumor microenvironment; IL1RL1+ Treg cells couple with cancer-associated fibroblasts (CAFs) via the amphiregulin (AREG)-EGFR axis, where Treg-derived AREG promotes a profibrotic and immunosuppressive CAF functional state. Blockade of IL1RL1 signaling in Tregs enhanced antitumor activity of IL-33 and PD-1 blockade. |
Single-cell RNA-seq, in vivo AREG mAb blockade, genetic IL1RL1 deficiency in Tregs, tumor growth experiments, PD-1 combination treatment |
Science advances |
Medium |
37611111
|
| 2019 |
IL-33/ST2 signaling promotes mast cell (MC) accumulation and ST2-expressing TAM (tumor-associated macrophage) expansion, and in colorectal cancer (CRC) models, ST2+ TAMs are recruited via CXCR3 expression and exacerbate the immunosuppressive TME. ST2 depletion combined with anti-PD-1 resulted in profound CRC growth inhibition. |
ST2-KO mice, CRC preclinical models, CXCR3 expression analysis, IL-33 trap fusion protein treatment, combination anti-PD-1 therapy, flow cytometry |
JCI insight |
Medium |
32376804
|
| 2019 |
IL-33/ST2 signaling in glioblastoma cells activates NF-κB and promotes invasion by upregulating tenascin-C (TNC); blocking the IL-33-ST2-NF-κB pathway downregulated TNC production, and TNC knockdown reduced glioma cell invasiveness. |
IL-33 treatment and knockdown in glioma cells, NF-κB activation assays, TNC expression measurement, invasion assays in vitro and in vivo (xenograft), ST2 blockade |
Scientific reports |
Medium |
31889095
|
| 2019 |
IL1RL1 is dynamically expressed on Cbfb-MYH11+ leukemia stem cells (LSCs); IL-33 treatment increased serial replating ability and expression of pro-survival proteins in IL1RL1+ cells in vitro, and IL1RL1+ cells survived chemotherapy better than IL1RL1- cells in vivo. |
Cbfb-MYH11 knock-in mouse model, in vitro IL-33 stimulation with pro-survival protein measurement, in vivo chemotherapy survival comparison of IL1RL1+ vs IL1RL1- sorted cells |
Scientific reports |
Medium |
30742053
|
| 2023 |
IL-33-ST2 signaling promotes stemness specifically in subtypes of myeloid leukemia cells (CD34+ BCR/ABL1 CML; AML1/ETO, DEK/NUP214 AML) by activating Wnt, MAPK, and NF-κB signaling, and repressing Notch; Wnt signaling in turn upregulates ST2 expression forming a cell-autonomous loop. IL-33-ST2 signaling promoted resistance to nilotinib and standard chemotherapy. |
Cell lines and patient samples, ST2 surface abundance quantification, Wnt/MAPK/NF-κB/Notch signaling assays, LSC culture and in vivo mouse expansion assays, drug resistance assays |
Science signaling |
High |
37643244
|
| 2023 |
IL-33/ST2 signaling in endometrial stromal cells inhibits ferroptosis via the P38/JNK pathway, which downregulates the transcription factor ATF3, thereby preventing ATF3-mediated repression of SLC7A11 (system Xc- antiporter), resulting in increased SLC7A11 expression and protection from lipid peroxidation and ferroptosis. |
Co-culture of endometrial stromal cells with macrophages, IL-33/ST2 stimulation, erastin-induced ferroptosis assay, ATF3 knockdown/overexpression, SLC7A11 quantification, P38/JNK inhibition, endometriosis mouse model with IL-33 antibody and erastin |
Cell death & disease |
High |
37816731
|
| 2023 |
The IL1RL1 genetic variant rs1921622, located in an enhancer element, downregulates sST2 gene and protein levels; CRISPR-Cas9 genome editing confirmed this regulatory relationship. Reduced sST2 levels lower Alzheimer's disease risk in females carrying APOE-ε4, with sST2 modulating Aβ pathology through microglial activation and Aβ clearance. |
GWAS, CRISPR-Cas9 genome editing of rs1921622 enhancer, Mendelian randomization, transcriptome analysis, immunohistochemistry in human and mouse brain, microglial activation assays |
Nature aging |
High |
37117777
|
| 2022 |
Setd2 (H3K36 methyltransferase) epigenetically regulates IL1RL1 (ST2) expression in Treg cells by modulating activity of promoters and intragenic enhancers where H3K36me3 is deposited; Setd2 deficiency in Tregs specifically reduces GATA3+ST2+ intestinal tTreg cells, impairing their suppressive function. |
Foxp3-Cre Setd2 conditional knockout, flow cytometry, H3K36me3 ChIP analysis, gene expression profiling of IL1RL1 and GATA3, human Treg SETD2 manipulation |
Nature communications |
Medium |
36463230
|
| 2017 |
IL-33/ST2 pathway induces microglia to express IL-1β, which in turn stimulates IL-33 expression in oligodendrocytes, forming an amplification loop between IL-1β and IL-33 responsible for exacerbated neuroinflammation in experimental cerebral malaria; ST2-deficient mice did not develop cognitive defects or neurogenesis deficits seen in WT infected mice. |
ST2-knockout mice in P. berghei ANKA infection model, in vitro IL-33/ST2 stimulation of microglia and oligodendrocytes, IL-1β and IL-33 coculture experiments, cognitive testing, hippocampal neurogenesis analysis |
PLoS pathogens |
Medium |
28448579
|
| 2020 |
Cell-intrinsic ST2 signaling in ILC2s is non-redundant for their activation; conditional ablation of ST2 specifically in ILC2s (using Nmur1 iCre-eGFP) rendered them unresponsive to IL-33 (but not IL-25), reduced IL-5 and IL-13 production, impaired eosinophil homeostasis, blocked ILC2 expansion in allergic lung inflammation, and increased susceptibility to Nippostrongylus brasiliensis infection. |
Conditional ST2 knockout in ILC2s (Nmur1-iCre), allergic lung inflammation model (papain), N. brasiliensis infection model, flow cytometry, cytokine measurement, eosinophil counting |
Frontiers in immunology |
High |
37063913
|
| 2019 |
ST2 deficiency in a pressure overload (TAC) model leads to increased periarteriolar fibrosis, while IL-33 deficiency alone does not produce the same phenotype. This dissociation suggests that loss of ST2 signaling (rather than changes in IL-33 expression) drives periarteriolar fibrosis during pressure overload and aging. |
IL-33-knockout and ST2-knockout mice with TAC pressure overload, aged WT mice, histomorphometric periarteriolar fibrosis quantification, IL-33 and ST2 expression analysis |
Journal of molecular and cellular cardiology |
Medium |
30763587
|
| 2020 |
Bcl6 and Blimp1 reciprocally regulate the development of ST2+ Treg cells during allergic airway inflammation: Bcl6-deficient Tregs generate twice as many ST2+ Tregs (in a Blimp1-dependent manner); these ST2+ Tregs produce type 2 cytokines and strongly promote allergic airway inflammation, and ST2 is required for this exacerbated phenotype. |
Bcl6fl/fl Foxp3-Cre and Prdm1fl/fl Foxp3-Cre conditional knockout mice, house dust mite sensitization model, T cell transfer experiments, flow cytometry, cytokine measurement |
The Journal of allergy and clinical immunology |
High |
32179158
|
| 2004 |
A novel fourth splice variant of the ST2/IL1RL1 gene, ST2LV, was identified in chicken; ST2LV lacks the transmembrane domain of ST2L (due to alternative splicing) and is secreted as a soluble N-glycosylated protein (~69 kDa; ~53 kDa after deglycosylation) into culture supernatant. |
RT-PCR cloning, COS-7 cell transfection with radiolabeling, peptide-N-glycosidase F treatment, Western blotting |
Biochimica et biophysica acta |
Medium |
15566939
|
| 2023 |
CD69+ST2+ lung-resident TH2 memory cells develop within 5 days of initial allergen exposure in lung tissue and persist for ≥84 days; their development and long-term memory function require ST2 and IL-33 signaling but not TSLP receptor. These cells rapidly produce type 2 cytokines upon recall challenge without involvement of circulating T cells. |
Parabiosis model, intranasal OVA/Alternaria sensitization, flow cytometry with in vivo antibody labeling, ST2-knockout and IL-33-knockout mice, recall challenge experiments |
The Journal of allergy and clinical immunology |
High |
36720287
|