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We found a positive correlation between serum levels of interleukin-33 (IL-33) and the Montreal Cognitive Assessment (MoCA) score in patients with stable schizophrenia, as well as with specific sub-scores. Smoking appears to decrease serum levels of soluble IL-33 receptor, a suppressor of tumorigenicity (sST2), possibly resulting in IL-33’s indirect preservation of cognitive functioning.

As a decoy receptor, soluble ST2 (sST2) interferes with the function of the inflammatory cytokine interleukin (IL)-33. Decreased sST2 expression in colorectal cancer (CRC) cells promotes tumor growth via IL-33-mediated bioprocesses in the tumor microenvironment. In this study, we discovered that hypoxia reduced sST2 expression in CRC cells and explored the associated molecular mechanisms, including the expression of key regulators of ST2 gene transcription in hypoxic CRC cells. In addition, the effect of the recovery of sST2 expression in hypoxic tumor regions on malignant progression was investigated using mouse CRC cells engineered to express sST2 in response to hypoxia. Our results indicated that hypoxia-dependent increases in nuclear IL-33 interfered with the transactivation activity of GATA3 for ST2 gene transcription. Most importantly, hypoxia-responsive sST2 restoration in hypoxic tumor regions corrected the inflammatory microenvironment and suppressed tumor growth and lung metastasis. These results indicate that strategies targeting sST2 in hypoxic tumor regions could be effective for treating malignant CRC.

The alarmin IL-33 has been implicated in the pathology of immune-mediated liver diseases. IL-33 activates regulatory T cells (Tregs) and type 2 innate lymphoid cells (ILC2s) expressing the IL-33 receptor ST2. We have previously shown that endogenous IL-33/ST2 signaling activates ILC2s that aggravate liver injury in murine immune-mediated hepatitis. However, treatment of mice with exogenous IL-33 before induction of hepatitis ameliorated disease severity. Since IL-33 induces expression of amphiregulin (AREG) crucial for Treg function, we investigated the immunoregulatory role of the ST2 Treg/AREG axis in immune-mediated hepatitis. C57BL/6, ST2-deficient (Il1rl1 ) and Areg mice received concanavalin A to induce immune-mediated hepatitis. Foxp3Cre x ST2fl/fl mice were pre-treated with IL-33 before induction of immune-mediated hepatitis. Treg function was assessed by adoptive transfer experiments and suppression assays. The effects of AREG and IL-33 on ST2 Tregs and ILC2s were investigated . Immune cell phenotype was analyzed by flow cytometry. We identified IL-33-responsive ST2 Tregs as an effector Treg subset in the murine liver, which was highly activated in immune-mediated hepatitis. Lack of endogenous IL-33 signaling in Il1rl1 mice aggravated disease pathology. This was associated with reduced Treg activation. Adoptive transfer of exogenous IL-33-activated ST2 Tregs before induction of hepatitis suppressed inflammatory T-cell responses and ameliorated disease pathology. We further showed increased expression of AREG by hepatic ST2 Tregs and ILC2s in immune-mediated hepatitis. Areg mice developed more severe liver injury, which was associated with enhanced ILC2 activation and less ST2 Tregs in the inflamed liver. Exogenous AREG suppressed ILC2 cytokine expression and enhanced ST2 Treg activation . In addition, Tregs from Areg mice were impaired in their capacity to suppress CD4 T-cell activation . Moreover, application of exogenous IL-33 before disease induction did not protect Foxp3Cre x ST2fl/fl mice lacking ST2 Tregs from immune-mediated hepatitis. In summary, we describe an immunoregulatory role of the ST2 Treg/AREG axis in immune-mediated hepatitis, in which AREG suppresses the activation of hepatic ILC2s while maintaining ST2 Tregs and reinforcing their immunosuppressive capacity in liver inflammation.

Il1rl1 (also known as ST2) is a member of the IL-1 superfamily, and its only known ligand is IL-33. ST2 exists in two forms as splice variants: a soluble form (sST2), which acts as a decoy receptor, sequesters free IL-33, and does not signal, and a membrane-bound form (ST2), which activates the MyD88/NF-κB signaling pathway to enhance mast cell, Th2, regulatory T cell (Treg), and innate lymphoid cell type 2 functions. sST2 levels are increased in patients with active inflammatory bowel disease, acute cardiac and small bowel transplant allograft rejection, colon and gastric cancers, gut mucosal damage during viral infection, pulmonary disease, heart disease, and graft-versus-host disease. Recently, sST2 has been shown to be secreted by intestinal pro-inflammatory T cells during gut inflammation; on the contrary, protective ST2-expressing Tregs are decreased, implicating that ST2/IL-33 signaling may play an important role in intestinal disease. This review will focus on what is known on its signaling during various inflammatory disease states and highlight potential avenues to intervene in ST2/IL-33 signaling as treatment options.

Introduction:Non-invasive tests that may improve clinical evaluation of pulmonary hypertension (PH) are needed. The purpose of this study was to assess the role of soluble ST2 (sST2) in patients with PH.Material and methods:A total of 57 patients with chronic thromboembolic PH and 43 patients with idiopathic arterial PH were enrolled in this study. All patients were evaluated for World Health Organization (WHO) functional class (FC), N-terminal prohormone B-type natriuretic peptide (NT-proBNP), troponin T (TnT), and hemodynamics. Plasma sST2 was assessed by an immu­nofluorescent in vitro diagnostic assay. All patients were followed up from the date of blood sampling. The endpoint was all-cause death.Results:The median sST2 concentration was 32.8 ng/ml (IQR: 21.6–48.5 ng/ml) in the whole study population. Significant differences were found between median sST2 in successive WHO FCs (FC II vs. FC III, p = 0.002; FC III vs. FC IV, p = 0.12; FC II vs. FC IV, p = 0.008). Significant correlations were found between sST2 and hemodynamic parameters: mean right atrial pressure (r = 0.56; p < 0.05), mean pulmonary artery pressure (r = 0.25; p < 0.05), cardiac index (r = –0.40; p < 0.05), pulmonary vascular resistance (r = 0.41; p < 0.05), and between sST2 and WHO FC (r = 0.36; p < 0.05), NT-proBNP (r = 0.55; p < 0.05), and TnT (r = 0.44; p < 0.05). sST2 concentration above the median was associated with worse clinical prognosis (p = 0.02, Kaplan-Meier).Conclusions:sST2 seems to be a marker of poor clinical prognosis in patients with PH.

Peritoneal fibrosis (PF) is an intractable complication of peritoneal dialysis (PD) that leads to peritoneal membrane failure. This study investigated the role of suppression of tumorigenicity (ST)2 in PF using patient samples along with mouse and cell‐based models. Baseline dialysate soluble (s)ST2 level in patients measured 1 month after PD initiation was 2063.4 ± 2457.8 pg/mL; patients who switched to haemodialysis had elevated sST2 levels in peritoneal effluent (1576.2 ± 199.9 pg/mL, P = .03), which was associated with PD failure (P = .04). Baseline sST2 showed good performance in predicting PD failure (area under the receiver operating characteristic curve = 0.780, P = .001). In mice with chlorhexidine gluconate‐induced PF, ST2 was expressed in fibroblasts and mesothelial cells within submesothelial zones. In primary cultured human peritoneal mesothelial cells (HPMCs), transforming growth factor‐β treatment increased ST2, fibronectin, β‐galactosidase and Snail protein levels and decreased E‐cadherin level. Anti‐ST2 antibody administration reversed the up‐regulation of ST2 and fibronectin expression; it also reduced fibrosis induced by high glucose (100 mmol/L) in HPMCs. Thus, high ST2 level in dialysate is a marker for fibrosis and inflammation during peritoneal injury, and blocking ST2 may be an effective therapeutic strategy for renal preservation.

Interleukin 33 (IL-33) is highly expressed in barrier sites, acting via the suppression of tumorigenicity 2 receptor (ST2). IL-33/ST2 axis has long been known to play a pivotal role in immunity and cell homeostasis by promoting wound healing and tissue repair. However, it is also involved in the loss of balance between extensive inflammation and tissue regeneration lead to remodeling, the hallmark of fibrosis. The aim of the current review is to critically evaluate the available evidence regarding the role of the IL-33/ST2 axis in organ fibrosis. The role of the axis in tissue remodeling is better understood considering its crucial role reported in organ development and regeneration. Generally, the IL-33/ST2 signaling pathway has mainly anti-inflammatory/anti-proliferative effects; however, chronic tissue injury is responsible for pro-fibrogenetic responses. Regarding pulmonary fibrosis mature IL-33 enhances pro-fibrogenic type 2 cytokine production in an ST2- and macrophage-dependent manner, while full-length IL-33 is also implicated in the pulmonary fibrotic process in an ST2-independent, Th2-independent fashion. In liver fibrosis, evidence indicate that when acute and massive liver damage occurs, the release of IL-33 might act as an activator of tissue-protective mechanisms, while in cases of chronic injury IL-33 plays the role of a hepatic fibrotic factor. IL-33 signaling has also been involved in the pathogenesis of acute and chronic pancreatitis. Moreover, IL-33 could be used as an early marker for ulcer-associated activated fibroblasts and myofibroblast trans-differentiation; thus one cannot rule out its potential role in inflammatory bowel disease-associated fibrosis. Similarly, the upregulation of the IL-33/ST2 axismay contribute to tubular cell injury and fibrosis via epithelial to mesenchymal transition (EMT) of various cell types in the kidneys. Of note, IL-33 exerts a cardioprotective role via ST2 signaling, while soluble ST2 has been demonstrated as a marker of myocardial fibrosis. Finally, IL-33 is a crucial cytokine in skin pathology responsible for abnormal fibroblast proliferation, leukocyte infiltration and morphologic differentiation of human endothelial cells. Overall, emerging data support a novel contribution of the IL-33/ST2 pathway in tissue fibrosis and highlight the significant role of the Th2 pattern of immune response in the pathophysiology of organ fibrosis.

As a classical prescription documented in the Treatise on Febrile Diseases, Gegen Qinlian Decoction (GGQLD) has been widely utilized for diarrhea and dysentery across history. Modern research indicates its potential efficacy in inflammatory bowel diseases, including ulcerative colitis (UC). To elucidate the pathways involved, this research examined how GGQLD reduces the severity of DSS-induced colitis in mice. To establish acute colitis, C57BL/6J mice were exposed to 3% DSS. Different doses of GGQLD, recombinant IL-33, or an IL-33-neutralizing antibody were then administered. The expression profiles of IL-33/ST2 pathway components and epithelial barrier proteins were investigated using immunostaining, qPCR, and Western blotting. Macrophage phenotypes were evaluated by flow cytometry, and cytokine secretion was assessed by ELISA. DSS exposure increased IL-33 expression, accompanied by a shift toward an M1-like macrophage phenotype and epithelial barrier damage. Recombinant IL-33 further exacerbated inflammation and permeability. In contrast, GGQLD and IL-33 neutralization alleviated colitis and reversed these changes. GGQLD treatment was accompanied by reduced M1-associated responses and an increased proportion of CD163 M2-like macrophages, together with decreased TNF-α and elevated IL-10 levels. In parallel, restoration of β-catenin and E-cadherin expression was observed, along with reduced ST2 expression. In a DSS-induced acute colitis mouse model, GGQLD alleviated disease severity and reduced IL-33/ST2 signaling activity. In parallel, macrophages displayed a shift toward an M2-like phenotype, accompanied by changes in inflammatory cytokine profiles and improved intestinal epithelial barrier integrity. These findings suggest that modulation of the IL-33/ST2 pathway may be involved in the therapeutic effects of GGQLD.

Cancer is initiated by mutations in critical regulatory genes; however, its progression to malignancy is aided by non-neoplastic cells and molecules that create a permissive environment known as the tumor stroma or microenvironment (TME). Interleukin 33 (IL-33) is a dual function cytokine that also acts as a nuclear factor. IL-33 typically resides in the nucleus of the cells where it is expressed. However, upon tissue damage, necrosis, or injury, it is quickly released into extracellular space where it binds to its cognate receptor suppression of tumorigenicity 2 (ST2)L found on the membrane of target cells to potently activate a T Helper 2 (Th2) immune response, thus, it is classified as an alarmin. While its role in immunity and immune-related disorders has been extensively studied, its role in tumorigenesis is only beginning to be elucidated and has revealed opposing roles in tumor development. The IL-33/ST2 axis is emerging as a potent modulator of the TME. By recruiting a cohort of immune cells, it can remodel the TME to promote malignancy or impose tumor regression. Here, we review its multiple functions in various cancers to better understand its potential as a therapeutic target to block tumor progression or as adjuvant therapy to enhance the efficacy of anticancer immunotherapies.

Phloretin, a glucose transporter (GLUT) inhibitor, has pleiotropic effects. The present study examined the effects of phloretin on the commitment of marrow stromal cells to adipocytes, using the mouse marrow stromal cell line ST2. Oil red O staining showed that treatment with phloretin 10–100 µM promoted lipid accumulation. Real-time PCR showed that phloretin significantly increased the expression of adipogenic markers, including PPARγ, C/EBPα, fatty acid synthase, fatty acid-binding protein 4, and adiponectin. Western blotting showed that phloretin inhibited ERK1/2 and JNK but activated p38 MAPK. Treatment with a MAPK/ERK kinase inhibitor and a JNK inhibitor enhanced adipogenesis, similar to phloretin. In contrast, a p38 MAPK inhibitor suppressed phloretin-induced adipogenesis. Although phloretin phosphorylated AMP-activated protein kinase (AMPK), co-incubation with an AMPK inhibitor did not block phloretin-induced adipogenesis. The 2-deoxyglucose colorimetric assay showed that phloretin and siRNA silencing of GLUT1 decreased glucose uptake. However, unlike phloretin treatment, GLUT1 silencing inhibited adipogenesis. In addition, phloretin enhanced adipogenesis in GLUT1 knocked-down cells. Taken together, phloretin induced adipogenesis of marrow stromal cells by inhibiting ERK1/2 and JNK and by activating p38 MAPK. The adipogenic effects of phloretin were independent of glucose uptake inhibition. Phloretin may affect energy metabolism by influencing adipogenesis and adiponectin expression.