ST2 Axis Research Articles

IL-33/ST2 correlates with severity of haemorrhagic fever with renal syndrome and regulates the inflammatory response in Hantaan virus-infected endothelial cells.

BackgroundHantaan virus (HTNV) causes a severe lethal haemorrhagic fever with renal syndrome (HFRS) in humans. Despite a limited understanding of the pathogenesis of HFRS, the importance of the abundant production of pro-inflammatory cytokines has been widely recognized. Interleukin 33 (IL-33) has been demonstrated to play an important role in physiological and pathological immune responses. After binding to its receptor ST2L, IL-33 stimulates the Th2-type immune response and promotes cytokine production. Depending on the disease model, IL-33 either protects against infection or exacerbates inflammatory disease, but it is unknown how the IL-33/ST2 axis regulates the immune response during HTNV infection.Methodology/Principal FindingsBlood samples were collected from 23 hospitalized patients and 28 healthy controls. The levels of IL-33 and soluble ST2 (sST2) in plasma were quantified by ELISA, and the relationship between IL-33, sST2 and the disease severity was analyzed. The role of IL-33/sST2 axis in the production of pro-inflammatory cytokines was studied on HTNV-infected endothelial cells. The results showed that the plasma IL-33 and sST2 were significantly higher in patients than in healthy controls. Spearman analysis showed that elevated IL-33 and sST2 levels were positively correlated with white blood cell count and viral load, while negatively correlated with platelet count. Furthermore, we found that IL-33 enhanced the production of pro-inflammatory cytokines in HTNV-infected endothelial cells through NF-κB pathway and that this process was inhibited by the recombinant sST2.Conclusion/SignificanceOur results indicate that the IL-33 acts as an initiator of the “cytokine storm” during HTNV infection, while sST2 can inhibit this process. Our findings could provide a promising immunotherapeutic target for the disease control.

Serum Concentrations of Interleukin-33 and its Soluble Receptor sST2 in Patients with Persistent Atrial Fibrillation

Objectives: Interleukin-33 (IL-33) is a new member of the IL-1 cytokine family, which is thought to be involved in the pathogenesis of various inflammatory diseases, through its soluble receptor ST2. There is increasing evidence that inflammation is a relevant player in structural atrial remodeling that represents the main mechanism for atrial fibrillation (AF) persistence. This study was designed to investigate the state of IL-33/ST2 axis serum concentrations in patients with persistent AF. Design and Methods: We investigated the concentrations of IL-33, its soluble ST2 receptors, and high-sensitivity C-reactive protein levels (hsCRP) in the sera of 92 patients with persistent atrial fibrillation, and 68 controls. Results: Serum concentrations of IL-33, sST2, and hsCRP were all significantly elevated in patients with persistent AF compared to controls (P <0.0001 for all). Moreover, serum IL-33 concentrations was positively correlated with the inflammatory marker hsCRP (r=0.606, P =0.002). Conclusion: These preliminary results may support the role of inflammation in AF pathogenesis and IL-33/sST2 axis may be involved in the inflammatory process in AF.

Interleukin-33/ST2 axis promotes epithelial cell transformation and breast tumorigenesis via upregulation of COT activity.

Cytokines of the interleukin-1 (IL-1) family, such as IL-1α/β and IL-18, have pleiotropic activities in innate and adaptive immune responses in host defense and diseases. Insight into their biological functions helped develop novel therapeutic approaches to treat human inflammatory diseases. IL-33 is an important member of the IL-1 family of cytokines and is a ligand of the ST2 receptor, a member of the IL-1 receptor family. However, the role of the IL-33/ST2 axis in tumor growth and metastasis of breast cancer remains unclear. Here, we demonstrate that IL-33 is a critical tumor promoter during epithelial cell proliferation and tumorigenesis in the breast. IL-33 dose- and time-dependently increased Cancer Osaka Thyroid (COT) phosphorylation via ST2-COT interaction in normal epithelial and breast cancer cells. The IL-33/ST2/COT cascade induced the activation of the MEK-ERK (MEK-extracellular signal-regulated kinase), JNK-cJun (cJun N-terminal kinase-cJun) and STAT3 (signal transducer and activator of transcription 3) signaling pathways, followed by increased AP-1 and stat3 transcriptional activity. When small interfering RNAs of ST2 and COT were introduced into cells, IL-33-induced AP-1 and stat3 activity were significantly decreased, unlike that in the control cells. The inhibition of COT activity resulted in decreased IL-33-induced epithelial cell transformation, and knockdown of IL-33, ST2 and COT in breast cancer cells attenuated tumorigenicity of breast cancer cells. Consistent with these observations, ST2 levels were positively correlated with COT expression in human breast cancer. These findings provide a novel perspective on the role of the IL-33/ST2/COT signaling pathway in supporting cancer-associated inflammation in the tumor microenvironment. Therapeutic approaches that target this pathway may, therefore, effectively inhibit carcinogenesis in the breast.

The Interleukin 33/ST2 Axis in Patients with Primary Sjögren Syndrome: Expression in Serum and Salivary Glands, and the Clinical Association

To evaluate the expression of interleukin 33 (IL-33) and its receptor in sera and salivary tissues of patients with primary Sjögren syndrome (pSS), and to investigate the association with clinical profiles. Serum IL-33 and soluble ST2 (sST2) of 55 patients with pSS and 48 controls were determined by ELISA and assessed for clinical correlation. The expression of IL-33/ST2 in salivary tissues was investigated by immunohistochemical staining and was further characterized by confocal microscopy. We also measured IL-33 production in salivary glandular epithelial cells by proinflammatory stimuli. Serum levels of IL-33 and sST2 were higher in patients with pSS compared to those in controls (p = 0.018 and p < 0.0001, respectively). Among patients with pSS, sST2 concentration was associated with thrombocytopenia (p = 0.029) and correlated with disease duration (p = 0.013) and the European League Against Rheumatism Sjögren Syndrome Disease Activity Index (p = 0.042). The expression of IL-33 and ST2 was elevated in salivary glands of patients with pSS with grade 2 inflammation, and diminished in advanced inflammation. In patients with pSS, IL-33 was mainly observed in epithelial and endothelial cells of glandular tissue. The production of IL-33 mRNA by salivary gland epithelial cell line increased under stimulation with interferon-γ. The expression of IL-33 and its receptor was elevated in sera and salivary tissues of patients with pSS. These results suggest that the IL-33/ST2 axis might have a role in the pathogenesis of pSS.

Associations between variants in IL-33/ST2 signaling pathway genes and coronary heart disease risk.

The IL-33/ST2 signaling pathway plays an important role in coronary artery disease (CHD); however, few studies have explored how variants in IL-33/ST2 genes influence CHD risk. Here, we examined the association between genetic variants in IL-33, ST2, and IL-1RAcP of the IL-33/ST2 axis and the risk of CHD. We conducted a case-controlled study with 1146 CHD cases and 1146 age- and sex-frequency-matched controls. Twenty-eight single nucleotide polymorphisms (SNPs) in IL-33, ST2, and IL-1RAcP were genotyped by Sequenom MassArray and TaqMan assay. Logistic regression was used to analyze these associations. The SNP rs4624606 in IL-1RAcP was nominally associated with CHD risk. The AA genotype was associated with a 1.85-fold increased risk of CHD (95% confidence interval (CI) = 1.01–3.36; p = 0.045) compared to the TT genotype. Further analysis showed that AA carriers also had a higher risk of CHD than TT + TA carriers (odds ratio (OR) = 1.85; 95% CI = 1.85–3.35; p = 0.043). However, no significant association was observed between variants in IL-33/ST2 genes and CHD risk. Further studies are needed to replicate our results in other ethnic groups with larger sample size.

O-031 YI IL-33/ST2 Axis Modulates Epithelial Repair and Gut Mucosal Wound Healing in DSS-Colitic Mice

O-031 YI IL-33/ST2 Axis Modulates Epithelial Repair and Gut Mucosal Wound Healing in DSS-Colitic Mice

Dynamics of the IL-33/ST2 network in the progression of human colorectal adenoma to sporadic colorectal cancer.

Most sporadic colorectal cancers (CRCs) develop from preformed adenomas. Cytokines are involved in the transition from adenoma to CRC. Interleukin-33 (IL-33) is a newly discovered proinflammatory cytokine belonging to the IL-1 cytokine family and involved in the development of chronic inflammation and cancer. The aim of this study was to evaluate the dynamics of the IL-33/ST2 axis during the sequence of progression from normal colorectum to adenoma to carcinoma and to investigate the association of IL-33 and ST2 expression with clinicopathological parameters and prognosis. The results demonstrated that the levels of IL-33 and ST2 in adenomas (n = 50), determined by real-time PCR, were significantly higher than those of normal controls (n = 30); the levels of both IL-33/ST mRNA in CRCs (n = 50) were higher than in normal controls but lower than in adenomas. Further analysis revealed that the expression level of ST2 in CRCs was associated with tumor/node/metastasis (TNM) stage. The log-rank test showed that neither the IL-33 nor the ST2 expression level was correlated with overall survival in patients with CRC. The increased expression of IL-33/ST2 in adenomas and CRC tissues was confirmed by immunohistochemistry and was observed in both the tumor stromal cells and adenomatous/cancerous cells. Notably, increased densities of IL-33-positive and ST2-positive microvessels were found in the stroma of adenomas and CRCs. In conclusion, increased expression of the IL-33/ST2 axis along the colorectal adenoma-carcinoma sequence might be involved in the neoplastic transformation via the participation of this axis in the regulation of angiogenesis.

IL-33/ST2 axis mediates resistance to EAE by promoting regulatory B and tolerogenic dendritic cells

BALB/c mice are resistant to EAE (experimental autoimmune encephalomyelitis) induction with MOG35–55 (Myelin Oligodendrocyte Glycoprotein). ST2 molecule is expressed on immune cells and its signaling is accompanied by accentuated ST2 response. We recently published that deletion of ST2 molecule abrogates resistance to EAE, as evaluated by clinical and histological findings. Adoptive transfer of ST2 KO lymphocytes restimulated with MOG35–55 induced clinical signs of the disease in ST2 KO and BALB/c mice.

Expression of interleukin-33 is correlated with poor prognosis of patients with squamous cell carcinoma of the tongue.

The aim of this study was to clarify the role of IL-33 in tumor progression. Surgical specimens from 81 patients with squamous cell carcinoma of the tongue were studied using immunohistochemistry. Primary tumor sections were analyzed for IL-33 and ST2 expression. To examine the influence of IL-33 on the microenvironment of the tumor, we determined the mast cell density (MCD) and microvessel density of the stroma. Patients with high IL-33 expression had a significantly worse prognosis (p=0.004). IL-33 expression was significantly elevated in patients with local and nodal recurrence (p=0.014 and p=0.019). ST2 expression was also associated with a worse prognosis (p=0.024) and was significantly elevated in patients with nodal recurrence (p=0.004). MCD was associated with worse prognosis (p=0.038) and correlated significantly with IL-33 expression (r=0.626, p<0.001). Micovessels in the stroma were significantly increased in the high IL-33 group (p<0.001). These data suggest that the IL-33/ST2 axis contributes to tumor aggressiveness and affects the tumor microenvironment. Immunohistochemical evaluation of IL-33 and ST2 is useful for identifying patients at a high risk for poor prognosis.

IL-33/ST2 axis promotes mast cell survival via BCLXL.

Mast cells (MC) are potent innate immune cells that accumulate in chronically inflamed tissues. MC express the IL-33 receptor IL-1 receptor-related protein ST2 at high level, and this IL-1 family cytokine both activates MC directly and primes them to respond to other proinflammatory signals. Whether IL-33 and ST2 play a role in MC survival remains to be defined. In skin-derived human MC, we found that IL-33 attenuated MC apoptosis without altering proliferation, an effect mediated principally through the antiapoptotic molecule B-cell lymphoma-X large (BCLXL). Murine MC demonstrated a similar mechanism, dependent entirely on ST2. In line with these observations, St2(-/-) mice exhibited reduced numbers of tissue MC in inflamed arthritic joints, in helminth-infected intestine, and in normal peritoneum. To confirm an MC-intrinsic role for ST2 in vivo, we performed peritoneal transfer of WT and St2(-/-) MC. In St2(-/-) hosts treated with IL-33 and in WT hosts subjected to thioglycollate peritonitis, WT MC displayed a clear survival advantage over coengrafted St2(-/-) MC. IL-33 blockade specifically attenuated this survival advantage, confirming IL-33 as the relevant ST2 ligand mediating MC survival in vivo. Together, these data reveal a cell-intrinsic role for the IL-33/ST2 axis in the regulation of apoptosis in MC, identifying thereby a previously unappreciated pathway supporting expansion of the MC population with inflammation.

THU0054 Interleukin-33/St2 Axis in Primary SjÖGren's Syndrome: Expression in Serum and Salivary Gland, and Clinical Association

BackgroundIL-33 and its receptor, ST2, are associated with many inflammatory disorders. However, the data on IL-33/ST2 in Sjögren's syndrome (SS) is very limited.ObjectivesTo evaluate the expression of IL-33 and its...

Tu1736 IL-33/ST2 Axis Modulates Epithelial Repair and Gut Mucosal Wound Healing in DSS-Colitic Mice

Background. Increasing evidence confirms that IL-33 and its receptor, ST2, are important factors in the pathogenesis of IBD. However, animal studies have yielded ambiguous results, reporting both pathogenic as well as protective functions. The aim of our study was to characterize and functionally evaluate the precise role of the IL-33/ST2 axis following acute epithelial injury and mucosal repair in dextran sodium sulphate (DSS)-induced colitic mice. Methods. 3% DSS was administered for 5d to C57/BL6 wild-type (WT), IL-33 KO and ST2 KO mice to induce colitis. DSS was then replaced with regular drinking water for 2 wks (recovery period). Another group of WT mice received DSS for 5d and IL-33 (33ug/kg, i.p.) or vehicle (VEH) every other day during the recovery period. Mice were sacrificed either after DSS challenge or after 1 or 2 wks of recovery; control mice (CT) not exposed to DSS were sacrificed at similar time points, at which time colons were harvested. Body weight, occult blood test, and stool consistency were measured daily to calculate Disease Activity Index (DAI), and endoscopic and histological evaluation of colons were performed using established scoring systems. IHC, qPCR and Western blots were done on full-thickness colons for IL-33 and ST2 localization, mRNA expression, and evaluation of protein isoforms, respectively. Results. DSS administered to WT mice resulted in increased body weight loss and DAI. More severe colitis was observed following DSS+1wk recovery vs. after 5d of DSS, which decreased after DSS+2wks recovery. IL-33 mRNA transcripts were dramatically elevated after DSS, and even more so following DSS+recovery vs. CT, but similar to CT after DSS+2wks recovery. ST2 mRNA expression was also increased after DSS+recovery vs. CT, while no difference was found between 5d of DSS challenge and CT and after DSS+2wks recovery. Full-length, bioactive IL33 (31 kDa), ST2L (76 kDa) and sST2 (52 kDa) were expressed in all experimental groups; the cleaved, less active form of IL33 (24 kDa) was increased in only DSS exposed mice vs. CT. IHC showed intense IL-33 and ST2 staining within the inflamed and ulceratedmucosa of DSS-treatedmice. ST2 staining was more evident during the recovery phase following DSS, notably localized to subepithelial myofibroblasts in close proximity to areas of re-epithelialization. Remarkably, both IL-33 and ST2 KO mice showed increased colonic inflammation after 2 wks recovery compared to after 5d DSS and vs also WT, suggesting the importance of IL-33/ST2 axis in mucosal healing. Likewise, IL33 treatment of WT mice resulted in increased body weight, reduced DAI, and decreased colonic inflammation after 2 wks recovery vs. VEH. Conclusions. Our results suggest that activation of the IL-33/ST2 axis promotes epithelial repair and mucosal healing following acute epithelial injury during DSS-induced colitis.

IL-33/ST2 promotes tissue mastocytosis under conditions of inflammation (CCR3P.219)

Abstract Mast cells (MC) are potent innate immune cells that accumulate in chronically inflamed tissues, where they have been implicated in multiple allergic and inflammatory diseases. MC express the IL-33 receptor ST2, and this new member of the IL-1 cytokine family is recognized as an important pathway both for direct MC activation and for priming MC to respond to other pro-inflammatory signals. However, IL-33 has no known role in tissue mastocytosis. Using primary MC cultured from human skin, we found that IL-33 did not alter MC proliferation but instead protected MC from apoptosis, principally through upregulation of the anti-apoptotic molecule BCLXL. Murine bone marrow-derived MC demonstrated a similar response to IL-33, dependent entirely upon ST2, allowing us to test the role of this biology in vivo. Mice lacking ST2 exhibited fewer peritoneal MC as well as reduced accumulation of MC in inflamed arthritic joints and helminth-infected intestine. Upon engraftment into the peritoneum, WT MC exhibited a clear, IL-33-mediated survival advantage over ST2-deficient MC, in particular after thioglycollate-induced peritonitis. Together, these data reveal a novel, cell-intrinsic role for the IL-33/ST2 axis in tissue mastocytosis, especially under conditions of local inflammation.

Anti-ST2 monoclonal antibody inhibits eosinophil infiltration in Angiostrongylus cantonensis-infected mice

Interleukin-33 (IL-33) could play an important role in the pathogenesis of angiostrongylosis. However, the role of IL-33/ST2 pathway in this parasitic infection is uncertain. C57BL/six mice were each infected with 35 Angiostrongylus cantonensis larvae. One group of mice received an intraperitoneal injection of anti-ST2 monoclonal antibody (mAb; 50μg) 3 days postinfection and subsequent booster shots of the same dose at 5-day intervals. Blood samples from each group were collected every week for assays. The level of IL-5 significantly decreased in the mAb-treated group, and the infiltration of eosinophils in the meninges was also significantly reduced. The IL-33/ST2 axis may play a crucial role in the pathogenesis of angiostrongylosis and the results of this study could be useful for the development of strategies to reduce the neurological damage caused by this parasitic infection.

P065 IL-33/ST2 axis modulates epithelial repair and gut mucosal wound healing in DSS-colitic mice

P065 IL-33/ST2 axis modulates epithelial repair and gut mucosal wound healing in DSS-colitic mice

1.64 Interleukin-33 suppresses experimental arthritis through promoting Foxp3+ regulatory T-cells and type-2 immune responses in mice

Background and ObjectivesInterleukin (IL)-33 is a new member of the IL-1 family that exerts pleiotropic activities in innate and adaptive immunity. With its receptor ST2, they have newly emerged as...

Potential involvement of the IL-33–ST2 axis in the pathogenesis of primary Sjögren's syndrome

ObjectivesTo investigate the role of the interleukin (IL)-33–ST2 axis in the pathophysiology of primary Sjögren's syndrome (pSS).MethodsSerum levels of IL-33 and sST2 were determined by ELISA. The expression of IL-33...

The role of IL-33 in host response to Candida albicans.

Background. Interleukin (IL) 33 is a recently identified pleiotropic cytokine that influences the activity of multiple cell types and orchestrates complex innate and adaptive immune responses. Methods. We performed an extensive review of the literature published between 2005 and 2013 on IL-33 and related cytokines, their functions, and their regulation of the immune system following Candida albicans colonization. Our literature review included cross-references from retrieved articles and specific data from our own studies. Results. IL-33 (IL-1F11) is a recently identified member of the IL-1 family of cytokines. Accumulating evidence suggests a pivotal role of the IL-33/ST2 axis in host immune defense against fungal pathogens, including C. albicans. IL-33 induces a Th2-type inflammatory response and activates both innate and adaptive immunity. Studies in animal models have shown that Th2 inflammatory responses have a beneficial role in immunity against gastrointestinal and systemic infections by Candida spp. Conclusions. This review summarizes the most important clinical studies and case reports describing the beneficial role of IL-33 in immunity and host defense mechanisms against pathogenic fungi. The finding that the IL-33/ST2 axis is involved in therapeutic target has implications for the prevention and treatment of inflammatory diseases, including acute or chronic candidiasis.

Role of IL-33 and its receptor in T cell-mediated autoimmune diseases.

Interleukin-33 (IL-33) is a new cytokine of interleukin-1 family, whose specific receptor is ST2. IL-33 exerts its functions via its target cells and plays different roles in diseases. ST2 deletion and exclusion of IL-33/ST2 axis are accompanied by enhanced susceptibility to dominantly T cell-mediated organ-specific autoimmune diseases. It has been reported that IL-33/ST2 pathway plays a key role in host defense and immune regulation in inflammatory and infectious diseases. This review focuses on new findings in the roles of IL-33 and ST2 in several kinds of T cell-mediated autoimmune diseases.

The Physiopathological Role of IL-33: New Highlights in Bone Biology and a Proposed Role in Periodontal Disease

Interleukin-33 (IL-33) is a recently described member of the IL-1 family. IL-33 acts as an alarmin, chemoattractant, and nuclear factor. ST2, a member of the Toll-like receptor/IL-1R superfamily, the receptor of IL-33, triggers a plethora of downstream effectors and leads the activation of NFK-B, leading the expression of several genes. IL-33 and ST2 are expressed in the majority of cell types, and the IL-33/ST2 axis has a role in immune response, bone homeostasis, and osteoclastogenesis. Several studies show opposite roles of IL-33 in osteoclastogenesis and the implication in bone biology. Few works studied the role of IL-33 in periodontal disease, but we hypothesize a possible role of IL-33 in periodontal disease and bone loss.