Affinage

IL1RL1

Interleukin-1 receptor-like 1 · UniProt Q01638

Length
556 aa
Mass
63.4 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL1RL1 encodes the IL-33 receptor system, producing both the transmembrane receptor ST2L and a soluble decoy isoform sST2, and serves as a central regulator of type 2 immunity, tissue homeostasis, fibrosis, and inflammatory disease across immune, stromal, and epithelial cell types. ST2L heterodimerizes with IL-1RAcP to transduce IL-33 signals through NF-κB, JNK, and p38 MAPK — but not ERK1/2 — to drive context-dependent outcomes including ILC2 activation, mast cell survival via BCLXL, Treg amphiregulin production, macrophage metabolic reprogramming, and anti-osteoclastogenic responses, while its intracellular TIR domain also sequesters MyD88/Mal to attenuate TLR signaling (PMID:20406635, PMID:24982172, PMID:37063913, PMID:26598236, PMID:30774633). sST2 functions as a soluble decoy that sequesters IL-33, but also independently activates cardiac fibroblasts through NRP-1/NF-κB to promote fibrosis, and is produced by mast cells, pneumocytes under mechanical strain, and tumor cells under nuclear FAK–IL-33 control (PMID:17492053, PMID:32664340, PMID:30562096, PMID:29208683). Genetic variants in IL1RL1 regulatory and TIR-coding regions modulate sST2 levels and IL-33 signaling strength through feedback loops, with GWAS-validated enhancer variants influencing Alzheimer's disease risk via microglial amyloid-beta clearance (PMID:23999434, PMID:32324168, PMID:37117777).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 High

    Cloning human ST2L resolved the gene structure of IL1RL1, establishing that alternative processing generates both a 556-aa transmembrane receptor (ST2L) and a soluble isoform (sST2) with differential tissue expression.

    Evidence cDNA cloning, genomic sequencing, RT-PCR, and flow cytometry on stable transfectants

    PMID:10936050

    Open questions at the time
    • Ligand identity was unknown at this stage
    • Signaling pathway downstream of ST2L was undefined
    • Regulatory mechanisms controlling isoform ratio were not addressed
  2. 2007 High

    Identification of IL-33 as the functional ligand for ST2L, and demonstration that sST2 acts as a decoy receptor, established the core signaling axis; ST2-deficient mice showed that this pathway protects against cardiac hypertrophy and fibrosis under pressure overload by inhibiting NF-κB.

    Evidence Recombinant IL-33 treatment, ST2−/− mice with transverse aortic constriction, NF-κB reporter assays, echocardiography

    PMID:17492053

    Open questions at the time
    • Downstream kinase cascades beyond NF-κB were not dissected
    • Whether sST2 had IL-33-independent functions was unknown
    • Cell-type-specific contributions in the heart were not resolved
  3. 2008 High

    Discovery that IL-1β induces de novo ST2L expression on dendritic cells, where it suppresses TLR/CD40 maturation responses, established ST2L as an inducible negative regulator of innate immune activation.

    Evidence ST2−/− mouse-derived DCs, rapamycin conditioning, flow cytometry for CD86, TLR/CD40 stimulation assays

    PMID:18566370

    Open questions at the time
    • Whether ST2L-mediated suppression was ligand-dependent or constitutive was not resolved
    • Intracellular mechanism of maturation resistance was not identified
  4. 2010 High

    Mapping downstream signaling showed IL-33/ST2L activates NF-κB, JNK, and p38 MAPK but not ERK1/2, with NF-κB specifically required for IL-13 production, resolving the pathway hierarchy.

    Evidence Pharmacological kinase inhibitors and IKK-2 shRNA knockdown in KU812 basophil-like cells

    PMID:20406635

    Open questions at the time
    • Whether this pathway hierarchy applies in non-basophil lineages was untested
    • Upstream adaptor recruitment mechanisms were not defined biochemically
  5. 2011 Low

    Computational modeling predicted that ST2L's TIR domain sequesters MyD88 and Mal via the BB-loop, offering a structural explanation for ST2L-mediated inhibition of TLR2/TLR4 signaling.

    Evidence Homology modeling, molecular dynamics simulation, and protein-protein docking (in silico only)

    PMID:21897866

    Open questions at the time
    • No experimental validation of the predicted TIR–MyD88/Mal interaction was provided
    • Binding affinities and competition kinetics were not measured
    • Mutagenesis of the BB-loop was not performed
  6. 2013 High

    GWAS linked IL1RL1 coding SNPs in the TIR domain to circulating sST2 levels and revealed a feedback loop: TIR domain missense variants enhance IL-33 signaling through ST2L, which in turn induces IL-33 expression and sST2 production, establishing genetic control of the IL-33/ST2 axis.

    Evidence GWAS in 2,991 Framingham participants with cell-culture functional assays for five missense variants

    PMID:23999434

    Open questions at the time
    • Whether these variants alter disease outcomes was not causally demonstrated
    • Structural basis for altered TIR signaling was not resolved
  7. 2014 High

    Two studies established cell-type-specific roles: IL-33/ST2 promotes mast cell survival via BCLXL upregulation (cell-intrinsic, confirmed by co-engraftment), and drives breast epithelial transformation through a COT/MEK-ERK/JNK/STAT3 cascade, revealing context-dependent downstream pathway usage.

    Evidence ST2−/− mast cell adoptive transfer with IL-33 neutralization; siRNA knockdown of ST2/COT with transformation and xenograft assays

    PMID:24982172 PMID:25531326

    Open questions at the time
    • Whether COT is a general mediator of ST2L signaling or specific to epithelial transformation was not tested
    • How ST2L simultaneously activates NF-κB in some cells and COT/STAT3 in others was unexplained
  8. 2015 High

    Three concurrent studies expanded the biological scope: mast cells were identified as a major inducible source of sST2 during anaphylaxis; IL-33/ST2 was shown to have anti-osteoclastogenic effects via pro-apoptotic gene induction; and ST2 blockade in hemophagocytic lymphohistiocytosis reduced pathogenic T-cell hyperactivation, demonstrating diverse protective and pathogenic roles.

    Evidence MC-deficient mice in anaphylaxis model; ST2−/− mice with mechanical bone loading and in vitro osteoclast assays; ST2 blockade in Prf1−/− LCMV infection model

    PMID:26256265 PMID:26518437 PMID:26598236

    Open questions at the time
    • Molecular basis for anti-osteoclastogenic transcriptional program was not fully defined
    • Whether sST2 released during anaphylaxis has functional regulatory consequences was not established
  9. 2017 High

    Three distinct regulatory mechanisms were uncovered: nuclear FAK–IL-33 complexes interact with chromatin modifiers (TAF9, WDR82, BRD4) to drive CCL5 and sST2 expression in tumors enabling immune evasion; IL-33/ST2 amplifies neuroinflammation through an oligodendrocyte–microglia IL-1β feedback loop in cerebral malaria; and CLOCK transcription factor binds the ST2 promoter to impose circadian gating of mast cell IL-33 responses.

    Evidence Nuclear Co-IP/MS with syngeneic tumor depletion experiments; ST2−/− cerebral malaria model with co-culture; ChIP of CLOCK at ST2 promoter in Clock-mutant mice

    PMID:28259547 PMID:28448579 PMID:29208683

    Open questions at the time
    • How nuclear FAK–IL-33 complex is assembled and whether it operates outside SCC was unknown
    • Whether circadian ST2 regulation extends beyond mast cells was not tested
  10. 2018 High

    Identification of alveolar type II pneumocytes as a major source of sST2 under mechanical strain explained why the lung is a dominant contributor to circulating sST2 in heart failure, linking mechanical sensing to the IL-33/ST2 decoy system.

    Evidence Ischemic heart failure model, primary human type II pneumocyte cultures with mechanical strain, tissue mRNA/protein quantification

    PMID:30562096

    Open questions at the time
    • Mechanosensory pathway upstream of sST2 induction in pneumocytes was not defined
    • Relative contribution of lung vs. cardiac sST2 to systemic levels was not quantified precisely
  11. 2020 High

    Multiple 2019–2020 studies refined both signaling and regulation: sST2 was shown to activate cardiac fibroblasts via NRP-1/NF-κB independently of IL-33 sequestration; TGF-β/MEK was found to program ILC2 development by upregulating ST2; IL-33/ST2 was shown to regulate macrophage metabolic reprogramming (shifting OXPHOS vs. glycolysis via PGC1α); TIR domain haplotype SNPs selectively modulate IL-33 but not TLR signaling; and helminth-derived HpBARI was identified as a high-affinity ST2 antagonist blocking IL-33 responses.

    Evidence NRP-1 knockdown in human cardiac fibroblasts with proteomics; conditional TGF-βRII KO; St2−/− BMDM metabolic profiling; primary bronchial epithelial signaling assays; biochemical binding and mouse asthma model with HpBARI

    PMID:30774633 PMID:31911623 PMID:32324168 PMID:32420871 PMID:32664340

    Open questions at the time
    • Whether NRP-1-mediated fibrosis pathway operates in vivo in human heart failure was not directly shown
    • Whether metabolic reprogramming is the primary effector of ST2 in macrophage polarization or a secondary consequence was unclear
  12. 2022 High

    Epigenetic and genetic control of IL1RL1 expression was clarified: Setd2-deposited H3K36me3 at IL1RL1 promoter/enhancer regions was shown to be required for ST2 expression in intestinal Treg cells, and a GWAS-validated enhancer variant (rs1921622) was demonstrated by CRISPR editing to causally regulate sST2 levels, with decreased sST2 reducing Alzheimer's disease risk through enhanced microglial Aβ clearance.

    Evidence Foxp3Cre Setd2 conditional KO with H3K36me3 ChIP-seq; GWAS with CRISPR-Cas9 enhancer editing and Mendelian randomization in AD cohorts

    PMID:36463230 PMID:37117777

    Open questions at the time
    • Whether Setd2-dependent ST2 regulation applies to non-Treg immune cells was not tested
    • Whether sST2 reduction is protective in AD independently of APOE-ε4 status and sex requires further delineation
  13. 2023 High

    Cell-type-specific conditional deletion proved that ILC2-intrinsic ST2 is essential for IL-33-driven type 2 immunity including eosinophil homeostasis and helminth defense; separately, IL-33/ST2 was shown to inhibit ferroptosis in endometrial stromal cells via P38/JNK suppression of ATF3 and upregulation of SLC7A11; and oxidised IL-33 was found to signal through RAGE/EGFR independently of ST2 in airway epithelium.

    Evidence Nmur1-iCre conditional ST2 KO in ILC2s with allergy and infection models; macrophage–stromal co-culture with ferroptosis readouts; Co-IP of IL-33ox with RAGE/EGFR in ALI epithelial cultures with scRNA-seq

    PMID:37063913 PMID:37442582 PMID:37816731

    Open questions at the time
    • Whether the RAGE/EGFR pathway activated by oxidised IL-33 interacts with or substitutes for canonical ST2 signaling in vivo is unknown
    • Ferroptosis regulation by ST2 has only been shown in endometriosis context
  14. 2024 High

    Recent work extended the IL-33/ST2 axis to new tissue contexts: NF-κB drives a positive-feedback loop (IL-33/NF-κB/ST2L/Rab37) for ST2L membrane trafficking in M2 macrophages that limits chemotherapy efficacy in lung cancer; and dual IL1RL1/IL-33 knockout in periodontitis models demonstrated a protective role of this axis in limiting acute inflammatory bone destruction by regulating macrophage polarization.

    Evidence NF-κB promoter assays and Rab37 trafficking studies with in vivo tumor models; IL1RL1−/− and IL-33−/− mouse periodontitis with micro-CT and flow cytometry

    PMID:38548743 PMID:38778059

    Open questions at the time
    • Rab37-mediated trafficking mechanism has not been validated outside the M2 macrophage system
    • Whether ST2 protective function in periodontitis is direct on stromal cells or indirect through immune modulation is not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for TIR domain variant-specific modulation of IL-33 vs. TLR signaling; how cell-type-specific co-receptor or adaptor availability determines divergent downstream pathway usage (NF-κB vs. COT/STAT3 vs. ERK); the in vivo significance of sST2's IL-33-independent NRP-1 fibrosis pathway in human disease; and the functional interplay between canonical ST2 signaling and the oxidised-IL-33/RAGE/EGFR axis.
  • No crystal structure of the full ST2L–IL-1RAcP–IL-33 signaling complex with TIR domain resolution
  • Mechanism determining cell-type-specific pathway selection downstream of ST2L is undefined
  • sST2 NRP-1 pathway lacks in vivo human validation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0098772 molecular function regulator activity 5 GO:0060090 molecular adaptor activity 2
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 3 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-168256 Immune System 6 R-HSA-1643685 Disease 5 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9909396 Circadian clock 1
Partners
AGEREGFRFAKIL1RAPIL33MYD88NRP1RAB37
Complex memberships
Nuclear FAK–IL-33–chromatin modifier complexST2L/IL-1RAcP receptor complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 IL-33 is a functional ligand for the transmembrane receptor ST2L (IL1RL1); sST2 functions as a soluble decoy receptor that blocks IL-33/ST2L signaling. IL-33 is predominantly synthesized by cardiac fibroblasts under mechanical stress, acts on cardiomyocytes in a paracrine manner to antagonize hypertrophy via inhibition of NF-κB nuclear binding activity, and ST2-deficient mice develop greater hypertrophy, fibrosis, and reduced survival after pressure overload. Recombinant protein treatment, ST2-/- mouse model with transverse aortic constriction, NF-κB reporter assays, histology, echocardiography The Journal of clinical investigation High 17492053
2000 Human ST2L cDNA was cloned; the gene IL1RL1 contains 13 exons spanning 40 kb on chromosome 2q and encodes a 556-amino-acid membrane-bound protein (ST2L) with 67% identity to mouse ST2L. The soluble isoform (sST2) and ST2L are differentially expressed. Cell-surface expression of ST2L was confirmed on stable transfectants. cDNA cloning, genomic sequencing, RT-PCR tissue distribution, stable transfection with flow cytometry confirmation Genomics High 10936050
2013 Common genetic variants (SNPs) within IL1RL1 drive variation in circulating sST2 levels; five missense variants map to the intracellular TIR domain of ST2L and, in cell culture, increase sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness via ST2L, establishing a feedback loop between ST2L signaling and sST2 production. GWAS in 2,991 Framingham Offspring Cohort participants, cell culture missense variant functional assays (sST2 ELISA, IL-33 measurement) The Journal of clinical investigation High 23999434
2010 IL-33 activates NF-κB, JNK, and p38 MAPK—but not ERK1/2—signaling pathways through ST2L; IL-33-induced IL-13 production was specifically regulated through NF-κB (confirmed by IKK-2 inhibition and IKK-2 shRNA knockdown), not JNK or p38 MAPK, in the human basophil-like KU812 cell line constitutively expressing ST2L. Pharmacological kinase inhibitors, shRNA knockdown of IKK-2, cytokine ELISA, pathway reporter assays in KU812 cells Experimental cell research High 20406635
2008 IL-1β produced by rapamycin-conditioned dendritic cells (RAPA-DC) drives de novo expression of the transmembrane receptor ST2L (IL1RL1) on DCs; ST2L upregulation suppresses TLR and CD40 responsiveness (maturation resistance), as RAPA-DC from ST2-/- mice showed higher CD86 expression and greater sensitivity to maturation stimuli. ST2-/- mouse-derived DC, in vitro and in vivo rapamycin conditioning, flow cytometry for CD86, functional TLR/CD40 stimulation assays Journal of immunology High 18566370
2014 IL-33 promotes mast cell survival via ST2 by upregulating the anti-apoptotic molecule BCLXL. In vivo, ST2-deficient mice had fewer tissue mast cells in inflamed arthritic joints, helminth-infected intestine, and normal peritoneum; co-engraftment experiments confirmed a cell-intrinsic, IL-33-dependent survival advantage for ST2-expressing mast cells. ST2-/- mouse model, peritoneal mast cell transfer, in vivo IL-33 blockade, flow cytometry for BCLXL and apoptosis markers Proceedings of the National Academy of Sciences of the United States of America High 24982172
2011 ST2L (IL1RL1) negatively regulates TLR2 and TLR4 signaling by sequestering the adaptor proteins MyD88 and Mal (TIRAP) via its intracellular TIR domain, primarily through the BB-loop region, thereby attenuating downstream inflammatory signaling. Computational homology modeling of TIR domains, molecular dynamics simulation, protein-protein docking analysis (in silico) PloS one Low 21897866
2017 Nuclear FAK promotes expression of IL-33 and sST2 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 activate NF-κB and induce CCL5 expression. sST2 sequesters extracellular IL-33 in the tumor microenvironment to evade anti-tumor immunity. Depletion of FAK, IL-33, or sST2 caused tumor regression dependent on CD8+ T cells. Nuclear FAK co-immunoprecipitation with IL-33, MS identification of interactors, syngeneic tumor implantation with CD8+ T cell co-depletion, shRNA knockdown Science signaling High 29208683
2020 TGF-β signaling through TGF-β receptor II is required for the development of ILC2 progenitors and upregulates IL1RL1 (ST2) expression in ILC2 progenitors and CHILP cells at least partially through the MEK-dependent pathway, thereby programming ILC2 development. Conditional TGF-βRII knockout in bone marrow progenitors, flow cytometry for ILC subsets, MEK inhibitor treatment Nature communications High 31911623
2015 Activated mast cells (via FcεRI or ST2) produce and release sST2 as a significant inducible source; antigen and IL-33 act synergistically with SCF to induce sST2 secretion. FcεRI-mediated sST2 production is independent of autocrine MC-derived IL-33, and circulating sST2 rises during anaphylaxis in an MC-dependent manner in mice. Human and mouse BMMC cultures, FcεRI crosslinking, IL-33 stimulation, sST2 ELISA, in vivo anaphylaxis model with MC-deficient mice European journal of immunology High 26256265
2012 Soluble ST2 (sST2) protein, when internalized into monocyte-derived dendritic cells, suppresses LPS-induced cytokine production and inhibits naive T cell proliferation by a noncanonical mechanism distinct from IL-33 sequestration. Human monocyte-derived DC culture, sST2 pre-treatment, LPS stimulation, cytokine ELISA, T cell proliferation assay, internalization imaging Cellular & molecular immunology Medium 22922442
2015 IL-33/ST2 signaling has anti-osteoclastogenic effects; IL-33 inhibits osteoclast differentiation and activity even in the presence of RANKL, and increases pro-apoptotic molecule expression (BAX, FAS, FASL, FADD, TRAIL, BID) in osteoclasts. ST2-deficient mice showed increased bone resorption and osteoclast numbers with reduced osteoblast counts and apoptotic cells following mechanical loading. ST2-/- mouse model with mechanical loading, microtomography, histomorphometry, in vitro osteoclast differentiation assay with IL-33 treatment, qPCR for apoptotic markers The American journal of pathology High 26598236
2017 IL-33/ST2 pathway in cerebral malaria drives neuroinflammation through an amplification loop: PbA infection triggers IL-33 expression by oligodendrocytes via ST2 pathway; IL-33/ST2 induces microglial IL-1β production, which in turn stimulates further IL-33 expression by oligodendrocytes. ST2-deficient mice did not develop cognitive defects and showed reduced neuroinflammatory markers. ST2-/- mouse model of experimental cerebral malaria, in vitro microglia-oligodendrocyte co-culture, cytokine qPCR, cognitive testing, hippocampal neurogenesis analysis PLoS pathogens High 28448579
2015 ST2 (IL1RL1) promotes T-cell hyperactivation in hemophagocytic lymphohistiocytosis; blockade of ST2 in LCMV-infected Prf1-/- mice improved survival and reduced IFNγ production by LCMV-specific CD8+ and CD4+ T cells, identifying IL-33 as the relevant ST2 ligand and danger signal amplifying immune dysregulation. ST2 blockade in Prf1-/- mouse model of FHL, LCMV infection, flow cytometry for IFNγ+ T cells, survival analysis Blood High 26518437
2019 In gastric cancer, CAF-derived IL-33 signals through ST2L on tumor cells to enhance migration and invasion via activation of the ERK1/2-SP1-ZEB2 pathway inducing EMT; TNF-α from GC cells induces IL-33 secretion by CAFs via TNFR2-NF-κB-IRF-1. Silencing IL-33 in CAFs or ST2L in GC cells inhibited peritoneal dissemination in nude mice. Co-culture model of GC cells and CAFs, siRNA knockdown of IL-33 and ST2L, ERK1/2 pathway inhibitors, nude mouse peritoneal dissemination model Oncogene High 31659258
2014 IL-33 promotes breast epithelial cell transformation and tumorigenesis via ST2-mediated activation of COT (Cancer Osaka Thyroid kinase) phosphorylation; the IL-33/ST2/COT cascade activates MEK-ERK, JNK-cJun, and STAT3 pathways. siRNA knockdown of ST2 or COT decreased IL-33-induced AP-1 and STAT3 transcriptional activity and inhibited tumorigenicity. siRNA knockdown of ST2 and COT, phosphorylation assays, transcriptional reporter assays, cell transformation assays, tumor xenograft models Oncogene High 25531326
2018 In lungs, sST2 is produced by alveolar type II pneumocytes in response to mechanical strain; in heart failure, the lung is a major source of circulating sST2, whereas ST2L/IL-33 signaling in the lung decreases while it increases favorably in myocardium. Experimental ischemic heart failure model with tissue sST2/ST2L/IL-33 mRNA and protein quantification, primary human type II pneumocyte cultures with mechanical strain, bronchial aspirate sST2 measurement, immunostaining Circulation. Heart failure High 30562096
2020 sST2 induces human cardiac fibroblast activation and collagen synthesis via upregulation of neuropilin-1 (NRP-1) through NF-κB; NRP-1 knockdown abolishes sST2-induced fibrosis, and pharmacological NF-κB inhibition restores NRP-1 levels and blocks profibrotic effects. This identifies a pathogenic mechanism for sST2 independent of IL-33 sequestration. Proteomics, NRP-1 knockdown, NF-κB pharmacological inhibition, collagen and fibrosis marker quantification in human cardiac fibroblasts, pressure-overload rat model correlation Cells High 32664340
2017 CLOCK transcription factor binds the ST2 (IL1RL1) promoter to regulate ST2 expression in mast cells in a circadian manner; Clock-mutant mice lack time-of-day variation in IL-33-induced cytokine production and ST2 expression, demonstrating that CLOCK temporally gates mast cell responses to IL-33 via ST2. Clock-mutant (ClockΔ19) mouse BMDMs, ChIP of CLOCK at ST2 promoter, cytokine production kinetics, in vivo IL-33-induced peritoneal neutrophil influx Allergology international High 28259547
2022 A genetic variant rs1921622 in an enhancer element of IL1RL1, identified by GWAS and validated by CRISPR-Cas9 editing, downregulates sST2 gene and protein levels. Decreased sST2 lowers AD risk and amyloid-beta pathology through modulation of microglial activation and Aβ clearance, specifically in APOE-ε4 female carriers. GWAS, CRISPR-Cas9 enhancer editing, Mendelian randomization, transcriptome and immunohistochemical analysis in human and mouse brain Nature aging High 37117777
2023 Macrophage-derived IL-33 signals through ST2 on endometrial stromal cells to inhibit ferroptosis via the P38/JNK pathway, which suppresses the negative transcription factor ATF3, thereby upregulating SLC7A11 (a ferroptosis inhibitor) and reducing lipid peroxidation and iron accumulation. Co-culture of macrophages and endometrial stromal cells, IL-33/ST2 stimulation and neutralization, P38/JNK pathway inhibitors, ATF3 and SLC7A11 quantification, ferroptosis readouts (ROS, lipid peroxidation), endometriosis mouse model Cell death & disease High 37816731
2023 Oxidised IL-33 (IL-33ox), which cannot bind ST2, forms a complex with RAGE and EGFR on airway epithelium to activate an ST2-independent signaling pathway that impairs wound closure and induces epithelial remodeling mimicking COPD pathology; neutralization of this pathway reverses deleterious traits in COPD epithelia. Co-immunoprecipitation of IL-33ox with RAGE/EGFR, air-liquid interface epithelial cultures, wound closure assays, bulk and single-cell RNA sequencing, IL-33-neutralizing antibody treatment of COPD ALI cultures The European respiratory journal High 37442582
2020 IL1RL1+ Treg cells signal via ST2 (IL1RL1) to produce amphiregulin (AREG), which acts on EGFR of cancer-associated fibroblasts to promote a profibrotic and immunosuppressive CAF state; the AREG/EGFR axis mediates Treg-CAF coupling that suppresses antitumor immunity and IL-33 anti-tumor effects. scRNA-seq of whole tumors, AREG blockade experiments, IL1RL1-conditional Treg models, combination IL-33 + AREG mAb tumor growth experiments Science advances High 37611111
2024 IL-33/ST2 (IL1RL1) axis plays a protective role in the acute phase of periodontitis; both Il1rl1- and Il33-deficient mice exhibit exacerbated bone loss with macrophage polarization toward a classically activated phenotype and increased neutrophil infiltration, establishing that IL-33/ST2 signaling in peri-root Thy-1.2- fibroblasts/stromal cells limits acute inflammatory bone destruction. IL1RL1-/- and IL-33-/- mouse ligature-induced periodontitis model, microtomography, histology, flow cytometry for macrophage polarization and neutrophil infiltration, qPCR Nature communications High 38548743
2020 IL1RL1 (ST2) loss in macrophages deficient in IL-33 signaling (St2-/-) results in increased mitochondrial number and activity (via PGC1α), increased oxidative phosphorylation, and decreased glycolysis following LPS stimulation, demonstrating that IL-33/ST2 pathway shapes macrophage polarization by regulating mitochondrial metabolic reprogramming. St2-/- and IL-33-overexpressing BMDM LPS stimulation, mitochondrial DNA copy number, oxygen consumption rate, extracellular acidification rate, mitochondria counts, gene expression Frontiers in immunology Medium 30774633
2024 IL-33 induces ST2L upregulation in M2 macrophages by activating NF-κB binding to the ST2L gene promoter; Rab37 (a small GTPase) mediates membrane trafficking of ST2L to the plasma membrane of M2 macrophages, forming a positive-feedback IL-33/NF-κB/ST2L/Rab37 loop that promotes M2 polarization and limits chemotherapy efficacy in lung cancer. NF-κB promoter binding assays, Rab37 functional studies in macrophages, neutralizing antibodies against IL-33 and ST2L, in vitro/in vivo tumor models with cisplatin combination Cell death & disease High 38778059
2023 Cell-intrinsic ST2 signals are required for ILC2 activation: conditional ablation of ST2 specifically in ILC2s (using Nmur1-iCre) abolished IL-33 responsiveness and limited IL-5/IL-13 production, eosinophil homeostasis, expansion during allergic lung inflammation, and type 2 immunity against Nippostrongylus brasiliensis infection. Nmur1-iCre conditional ST2 knockout in ILC2s, flow cytometry, cytokine measurement, papain-induced allergic lung inflammation, N. brasiliensis infection model Frontiers in immunology High 37063913
2020 The helminth protein HpBARI binds murine ST2 (IL1RL1) and inhibits its cell surface detection, preventing IL-33–ST2 interactions and blocking IL-33 responses in vitro and in an in vivo mouse asthma model; HpBARI_Hom2 also binds human ST2 with high affinity and blocks human PBMC responses to IL-33. Direct binding assays, ST2 cell-surface detection assays, in vitro IL-33 response inhibition, mouse asthma model, human PBMC IL-33 response blocking eLife High 32420871
2020 Lung-resident CD69+ST2+ TH2 memory cells develop after inhaled allergen exposure in an ST2/IL-33-dependent—but not TSLP-dependent—manner and persist for at least 84 days, enabling rapid type 2 cytokine production upon re-challenge without circulating T cell involvement. Parabiosis model, in vivo antibody labeling, flow cytometry, ST2-/- and IL-33-/- gene-deficient mice, intranasal OVA recall challenge The Journal of allergy and clinical immunology High 36720287
2022 Setd2 (H3K36 methyltransferase) supports GATA3+ST2+ intestinal thymic-derived Treg cells by facilitating expression of IL1RL1 through modulation of promoter and intragenic enhancer activity where H3K36me3 is deposited; loss of Setd2 in Treg cells impairs ST2 expression and Treg suppressive function in intestinal inflammation. Foxp3Cre-YFP Setd2fl/fl conditional KO, H3K36me3 ChIP-seq, IL1RL1 expression analysis, intestinal inflammation models Nature communications High 36463230
2020 IL1RL1 TIR signaling domain haplotype SNPs affect IL-33-driven NF-κB signaling without interfering with TLR signaling in bronchial epithelial cells, providing functional evidence that coding variants in the TIR domain selectively modulate IL-33 receptor signal transduction. Primary bronchial epithelial cell cultures, NF-κB signaling assays with IL-33 and TLR stimulation, genotyping of TIR domain SNPs JCI insight Medium 32324168

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. The Journal of clinical investigation 850 17492053
2008 The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nature reviews. Drug discovery 646 18827826
2015 The biology of ST2: the International ST2 Consensus Panel. The American journal of cardiology 237 25665766
2012 IL-33/ST2 axis in inflammation and immunopathology. Immunologic research 223 22392053
2008 Nonmyocardial production of ST2 protein in human hypertrophy and failure is related to diastolic load. Journal of the American College of Cardiology 199 19095135
2018 IL-33/ST2 Axis in Organ Fibrosis. Frontiers in immunology 176 30405626
2013 Decoding asthma: translating genetic variation in IL33 and IL1RL1 into disease pathophysiology. The Journal of allergy and clinical immunology 145 23380221
2004 T1/ST2--an IL-1 receptor-like modulator of immune responses. Cytokine & growth factor reviews 145 15110792
2015 The IL-33/ST2 axis: Role in health and disease. Cytokine & growth factor reviews 137 26271893
2020 Soluble ST2: A complex and diverse role in several diseases. Clinica chimica acta; international journal of clinical chemistry 111 32305537
2019 The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-α/IL-33/ST2L signaling promotes gastric cancer metastasis. Oncogene 111 31659258
2018 The Role of IL-33/ST2 Pathway in Tumorigenesis. International journal of molecular sciences 100 30205617
2011 Measurement of interleukin-33 (IL-33) and IL-33 receptors (sST2 and ST2L) in patients with rheumatoid arthritis. Journal of Korean medical science 99 21935266
2010 Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia. European journal of human genetics : EJHG 98 21150878
2013 A novel cardiac bio-marker: ST2: a review. Molecules (Basel, Switzerland) 96 24335613
2013 Common genetic variation at the IL1RL1 locus regulates IL-33/ST2 signaling. The Journal of clinical investigation 93 23999434
2014 IL-33/ST2 pathway contributes to metastasis of human colorectal cancer. Biochemical and biophysical research communications 89 25280997
2015 Soluble ST2--analytical considerations. The American journal of cardiology 85 25697919
2011 ST2 and IL-33 in pregnancy and pre-eclampsia. PloS one 82 21949719
2014 Interleukin-33/ST2 axis promotes epithelial cell transformation and breast tumorigenesis via upregulation of COT activity. Oncogene 78 25531326
2023 Role of IL-33-ST2 pathway in regulating inflammation: current evidence and future perspectives. Journal of translational medicine 77 38082335
2015 An antitumorigenic role for the IL-33 receptor, ST2L, in colon cancer. British journal of cancer 76 26679377
2015 Activated mast cells synthesize and release soluble ST2-a decoy receptor for IL-33. European journal of immunology 74 26256265
2015 Crucial and diverse role of the interleukin-33/ST2 axis in infectious diseases. Infection and immunity 71 25712928
2017 IL-33 and ST2 mediate FAK-dependent antitumor immune evasion through transcriptional networks. Science signaling 70 29208683
2014 IL-33/ST2 axis promotes mast cell survival via BCLXL. Proceedings of the National Academy of Sciences of the United States of America 70 24982172
2000 The cloning and nucleotide sequence of human ST2L cDNA. Genomics 69 10936050
2023 Oxidised IL-33 drives COPD epithelial pathogenesis via ST2-independent RAGE/EGFR signalling complex. The European respiratory journal 65 37442582
2008 IL-1beta-driven ST2L expression promotes maturation resistance in rapamycin-conditioned dendritic cells. Journal of immunology (Baltimore, Md. : 1950) 64 18566370
2022 IL-33/ST2 axis in autoimmune disease. Cytokine 60 36041312
2018 Pulmonary Production of Soluble ST2 in Heart Failure. Circulation. Heart failure 60 30562096
2017 Role of the IL-33-ST2 axis in sepsis. Military Medical Research 59 28168040
2015 The role of IL-33/ST2L signals in the immune cells. Immunology letters 57 25662624
2020 A helminth-derived suppressor of ST2 blocks allergic responses. eLife 54 32420871
2021 IL-33/ST2 as a potential target for tumor immunotherapy. European journal of immunology 53 34131922
2017 IL-33 receptor ST2 regulates the cognitive impairments associated with experimental cerebral malaria. PLoS pathogens 53 28448579
2011 In silico approach to inhibition of signaling pathways of Toll-like receptors 2 and 4 by ST2L. PloS one 53 21897866
2021 T reg cell-intrinsic requirements for ST2 signaling in health and neuroinflammation. The Journal of experimental medicine 52 33095261
2020 TGF-β induces ST2 and programs ILC2 development. Nature communications 52 31911623
2015 ST2 contributes to T-cell hyperactivation and fatal hemophagocytic lymphohistiocytosis in mice. Blood 52 26518437
2013 The IL-33-ST2L pathway is associated with coronary artery disease in a Chinese Han population. American journal of human genetics 52 24075188
2019 ST2/IL-33 signaling in cardiac fibrosis. The international journal of biochemistry & cell biology 50 31561019
2014 Phenotypic and genotypic association of epithelial IL1RL1 to human TH2-like asthma. The Journal of allergy and clinical immunology 50 25091434
2017 Emerging Roles of IL-33/ST2 Axis in Renal Diseases. International journal of molecular sciences 49 28387719
2020 Bcl6 and Blimp1 reciprocally regulate ST2+ Treg-cell development in the context of allergic airway inflammation. The Journal of allergy and clinical immunology 47 32179158
2018 IL-33 and Its Receptor ST2 after Inhaled Allergen Challenge in Allergic Asthmatics. International archives of allergy and immunology 45 29694974
2023 Amphiregulin couples IL1RL1+ regulatory T cells and cancer-associated fibroblasts to impede antitumor immunity. Science advances 44 37611111
2022 An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer's disease. Nature aging 42 37117777
2023 Macrophages originated IL-33/ST2 inhibits ferroptosis in endometriosis via the ATF3/SLC7A11 axis. Cell death & disease 41 37816731
2017 IL-33/ST2 Pathway as a Rational Therapeutic Target for CNS Diseases. Neuroscience 38 29175156
2022 Soluble ST2 Is a Sensitive and Specific Biomarker for Fulminant Myocarditis. Journal of the American Heart Association 37 35377184
2018 The IL-33 Receptor ST2 Regulates Pulmonary Inflammation and Fibrosis to Bleomycin. Frontiers in immunology 36 29988569
2018 ST2: Current status. Indian heart journal 36 30122246
2018 Role of the IL-33/ST2L axis in colorectal cancer progression. Cellular immunology 35 29329638
2017 IL-33-ST2 Axis in Liver Disease: Progression and Challenge. Mediators of inflammation 35 29180837
2020 Clinical value of soluble ST2 in cardiology. Advances in clinical and experimental medicine : official organ Wroclaw Medical University 34 33049127
2018 Interleukin-33 and ST2 Signaling in Tumor Microenvironment. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 34 30256696
2021 Pathophysiologic role of Interleukin-33/ST2 in Sjögren's syndrome. Autoimmunity reviews 33 33476812
2019 Deficiency in IL-33/ST2 Axis Reshapes Mitochondrial Metabolism in Lipopolysaccharide-Stimulated Macrophages. Frontiers in immunology 33 30774633
2019 The role of the IL-33/ST2 axis in autoimmune disorders: Friend or foe? Cytokine & growth factor reviews 33 31085085
2015 Osteoprotective Effects of IL-33/ST2 Link to Osteoclast Apoptosis. The American journal of pathology 33 26598236
2012 IL1RL1 gene variants and nasopharyngeal IL1RL-a levels are associated with severe RSV bronchiolitis: a multicenter cohort study. PloS one 33 22574108
2018 Critical Roles of IL-33/ST2 Pathway in Neurological Disorders. Mediators of inflammation 32 29507527
2015 ST2 in stable and unstable ischemic heart diseases. The American journal of cardiology 32 25678392
2023 The Role of IL-33/ST2 in COPD and Its Future as an Antibody Therapy. International journal of molecular sciences 31 37240045
2012 The ST2 pathway is involved in acute pancreatitis: a translational study in humans and mice. The American journal of pathology 30 22542450
2022 Setd2 supports GATA3+ST2+ thymic-derived Treg cells and suppresses intestinal inflammation. Nature communications 29 36463230
2020 ST2 Signaling in the Tumor Microenvironment. Advances in experimental medicine and biology 29 32060890
2017 Clock-dependent temporal regulation of IL-33/ST2-mediated mast cell response. Allergology international : official journal of the Japanese Society of Allergology 29 28259547
2023 ILC2 require cell-intrinsic ST2 signals to promote type 2 immune responses. Frontiers in immunology 27 37063913
2020 Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium. JCI insight 27 32324168
2013 The evolutionary role of the IL-33/ST2 system in host immune defence. Archivum immunologiae et therapiae experimentalis 27 23283516
2013 ST2 regulates allergic airway inflammation and T-cell polarization in epicutaneously sensitized mice. The Journal of investigative dermatology 27 23633023
2023 Lung-resident CD69+ST2+ TH2 cells mediate long-term type 2 memory to inhaled antigen in mice. The Journal of allergy and clinical immunology 26 36720287
2018 Genetic regulation of IL1RL1 methylation and IL1RL1-a protein levels in asthma. The European respiratory journal 26 29519908
2018 IL-33 Promotes the Development of Colorectal Cancer Through Inducing Tumor-Infiltrating ST2L+ Regulatory T Cells in Mice. Technology in cancer research & treatment 26 29950152
2024 The IL-33/ST2 axis is protective against acute inflammation during the course of periodontitis. Nature communications 25 38548743
2019 IL-33/ST2 axis promotes glioblastoma cell invasion by accumulating tenascin-C. Scientific reports 25 31889095
2016 Soluble ST2 and Galectin-3: What We Know and Don't Know Analytically. EJIFCC 25 27683536
2017 IL33 and IL1RL1 variants are associated with asthma and atopy in a Brazilian population. International journal of immunogenetics 24 28266165
2022 Soluble ST2 in coronary artery disease: Clinical biomarkers and treatment guidance. Frontiers in cardiovascular medicine 23 36225958
2012 Soluble ST2 protein inhibits LPS stimulation on monocyte-derived dendritic cells. Cellular & molecular immunology 23 22922442
2025 IL-33/ST2 axis in diverse diseases: regulatory mechanisms and therapeutic potential. Frontiers in immunology 22 39925809
2022 Profiling of Tregs across tissues reveals plasticity in ST2 expression and hierarchies in tissue-specific phenotypes. iScience 21 36093048
2020 The Interleukin-33/ST2 axis promotes glioma mesenchymal transition, stemness and TMZ resistance via JNK activation. Aging 21 32003751
2022 Hepatic pannexin-1 mediates ST2+ regulatory T cells promoting resolution of inflammation in lipopolysaccharide-induced endotoxemia. Clinical and translational medicine 20 35593197
2019 IL1RL1 is dynamically expressed on Cbfb-MYH11+ leukemia stem cells and promotes cell survival. Scientific reports 20 30742053
2019 Dysregulation of IL-33/ST2 signaling and myocardial periarteriolar fibrosis. Journal of molecular and cellular cardiology 20 30763587
2018 Interleukin-33 Receptor (ST2) Deficiency Improves the Outcome of Staphylococcus aureus-Induced Septic Arthritis. Frontiers in immunology 20 29867945
2015 Soluble ST2 and IL-33: Potential markers of endometriosis in the Tunisian population. Immunology letters 20 25977120
2020 Soluble St2 Induces Cardiac Fibroblast Activation and Collagen Synthesis via Neuropilin-1. Cells 19 32664340
2019 Correlation of Interleukin-33/ST2 Receptor and Liver Fibrosis Progression in Biliary Atresia Patients. Frontiers in pediatrics 19 31632941
2016 ST2L Transmembrane Receptor Expression: An Immunochemical Study on Endarterectomy Samples. PloS one 19 27223112
2010 KU812 cells provide a novel in vitro model of the human IL-33/ST2L axis: functional responses and identification of signaling pathways. Experimental cell research 19 20406635
2020 The Functional Roles of IL-33/ST2 Axis in Ocular Diseases. Mediators of inflammation 18 32908451
2018 IL-33 receptor (ST2) deficiency downregulates myeloid precursors, inflammatory NK and dendritic cells in early phase of sepsis. Journal of biomedical science 18 30001716
2016 IL‑33/ST2 pathway in a bleomycin‑induced pulmonary fibrosis model. Molecular medicine reports 18 27358001
2024 IL-33/NF-κB/ST2L/Rab37 positive-feedback loop promotes M2 macrophage to limit chemotherapeutic efficacy in lung cancer. Cell death & disease 17 38778059
2018 ST2 regulates bone loss in a site-dependent and estrogen-dependent manner. Journal of cellular biochemistry 17 30011081
2015 Potential role of the IL-33/ST2 axis in celiac disease. Cellular & molecular immunology 17 26343805