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    ST2 may not be a useful predictor for incident cardiovascular events, heart failure and mortality. Hughes Maria F,Appelbaum Sebastian,Havulinna Aki S,Jagodzinski Annika,Zeller Tanja,Kee Frank,Blankenberg Stefan,Salomaa Veikko, Heart (British Cardiac Society) OBJECTIVES:We hypothesised that soluble ST2 (sST2) levels can identify people with elevated risk of subsequent cardiovascular disease (CVD) and add to existing risk prediction algorithms. BACKGROUND:ST2 is a receptor for the inflammatory cytokine IL33. Increased sST2 levels have been associated with heart failure and death in acute myocardial infarction patients and in the general population. METHODS:We measured high-sensitivity sST2 in 8444 men and women (25-74 years) from the FINRISK97 prospective population cohort. Cox proportional hazards modelling evaluated the ability of sST2 to predict fatal and non-fatal heart failure, CVD (coronary heart disease, stroke), diabetes, and death over 15 years follow-up. Discrimination and reclassification statistics for 10-year absolute risks compared the ability of sST2 to improve upon Framingham risk factors (FRF), N-terminal pro-brain natriuretic peptide (NT-proBNP), renal function (eGFR) and prevalent valvular heart disease (VHD). RESULTS:sST2 showed suggestive but non-significant associations with heart failure {(HR per 1 SD of log sST2 1.06; 95% CI 0.96 to 1.17 (562 events))}, and with CVD (1.01 95% CI 0.94 to 1.08) (914 events) after adjustment for FRF, NT-proBNP, eGFR and VHD. sST2 significantly predicted death from all causes following similar adjustment ({HR 1.09 (95% CI 1.01 to 1.19) (974 events))}. No improvement in the c-index was observed for models adding sST2 to the risk factors. CONCLUSIONS:In a healthy general population from Finland, sST2 did not improve long-term prediction of cardiovascular events including heart failure or all-cause mortality. 10.1136/heartjnl-2014-305968
    IL-33 at the Crossroads of Metabolic Disorders and Immunity. Tu Lei,Yang Lijing Frontiers in endocrinology As a cytokine in interleukin-1(IL-1) family, interleukin-33(IL-33) usually exists in the cytoplasm and cell nucleus. When the cells are activated or damaged, IL-33 can be secreted into extracellular and regulate the functions of various immune cells through binding to its specific receptor suppression of tumorigenicity 2 (ST2). Except regulating the function of immune cells including T cells, B cells, dendritic cells (DCs), macrophages, mast cells, and innate lymphoid cells, IL-33 also plays an important role in metabolic diseases and has received an increasing attention. This review summarizes the regulation of IL-33 on different immune cells in lipid metabolism, which will help to understand the pathology of abnormal lipid metabolic diseases, such as atherosclerosis and type 2 diabetes. 10.3389/fendo.2019.00026
    Metformin Can Alleviate the Symptom of Patient with Diabetic Nephropathy Through Reducing the Serum Level of Hcy and IL-33. Zhang Ling,Niu Jiansheng,Zhang Xiumei,He Wanxia Open medicine (Warsaw, Poland) Background:Interleukin-33 (IL-33) and homocysteine (Hcy) were found to be up-regulated in patients with diabetic nephropathy (DN), and the present study aimed to investigate whether metformin (MT) can influence the serum levels of IL-33 and Hcy in patients with DN. Methods:Sixty patients with type 2 diabetes mellitus (DM) were divided into DM group (albumin: Alb <20 mg/L), DN group (Alb >20mg/L), and DN+ MT treatment group, with 20 cases in each group. Patients in each group were treated with insulin for 3 months, and patients in DN+MT group was treated with insulin+MT for 3 months. The serum levels of IL-33, urinary microalbumin excretion rate (UAE), body mass index (BMI), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), creatinine (Cr), cystatin C (CysC) and Hcy were measured before and after medication. Twenty normal subjects were involved as control. Results:BMI, Hcy and TC were reduced and HDL-C was increased of patients had been treated with metformin and insulin. UAE, Cr, Ccr and CysC had no differences before and after treatment. The serum level of IL-33 significantly up-regulated in patients with DN, and MT treatment significantly decreased the serum level of IL-33 in patients with DN. Conclusion:Metformin could alleviate the symptom of patient with DN through decreasing the serum level of IL-33 and Hcy. 10.1515/med-2019-0071
    IL-33 is a crucial amplifier of innate rather than acquired immunity. Oboki Keisuke,Ohno Tatsukuni,Kajiwara Naoki,Arae Ken,Morita Hideaki,Ishii Akina,Nambu Aya,Abe Takaya,Kiyonari Hiroshi,Matsumoto Kenji,Sudo Katsuko,Okumura Ko,Saito Hirohisa,Nakae Susumu Proceedings of the National Academy of Sciences of the United States of America IL-33, a member of the IL-1-related cytokines, is considered to be a proallergic cytokine that is especially involved in Th2-type immune responses. Moreover, like IL-1α, IL-33 has been suggested to act as an "alarmin" that amplifies immune responses during tissue injury. In contrast to IL-1, however, the precise roles of IL-33 in those settings are poorly understood. Using IL-1- and IL-33-deficient mice, we found that IL-1, but not IL-33, played a substantial role in induction of T cell-mediated type IV hypersensitivity such as contact and delayed-type hypersensitivity and autoimmune diseases such as experimental autoimmune encephalomyelitis. Most notably, however, IL-33 was important for innate-type mucosal immunity in the lungs and gut. That is, IL-33 was essential for manifestation of T cell-independent protease allergen-induced airway inflammation as well as OVA-induced allergic topical airway inflammation, without affecting acquisition of antigen-specific memory T cells. IL-33 was significantly involved in the development of dextran-induced colitis accompanied by T cell-independent epithelial cell damage, but not in streptozocin-induced diabetes or Con A-induced hepatitis characterized by T cell-mediated apoptotic tissue destruction. In addition, IL-33-deficient mice showed a substantially diminished LPS-induced systemic inflammatory response. These observations indicate that IL-33 is a crucial amplifier of mucosal and systemic innate, rather than acquired, immune responses. 10.1073/pnas.1003059107
    Cytokine Signaling in the Development and Homeostasis of Regulatory T cells. Toomer Kevin H,Malek Thomas R Cold Spring Harbor perspectives in biology Cytokine signaling is indispensable for regulatory T-cell (Treg) development in the thymus, and also influences the homeostasis, phenotypic diversity, and function of Tregs in the periphery. Because Tregs are required for establishment and maintenance of immunological self-tolerance, investigating the role of cytokines in Treg biology carries therapeutic potential in the context of autoimmune disease. This review discusses the potent and diverse influences of interleukin (IL)-2 signaling on the Treg compartment, an area of knowledge that has led to the use of low-dose IL-2 as a therapy to reregulate autoaggressive immune responses. Evidence suggesting Treg-specific impacts of the cytokines transforming growth factor β (TGF-β), IL-7, thymic stromal lymphopoietin (TSLP), IL-15, and IL-33 is also presented. Finally, we consider the technical challenges and knowledge limitations that must be overcome to bring other cytokine-based, Treg-targeted therapies into clinical use. 10.1101/cshperspect.a028597
    IL-33-driven ILC2/eosinophil axis in fat is induced by sympathetic tone and suppressed by obesity. Ding Xiaofeng,Luo Yan,Zhang Xing,Zheng Handong,Yang Xin,Yang Xuexian,Liu Meilian The Journal of endocrinology Group 2 innate lymphoid cells (ILC2s) in white adipose tissue (WAT) promote WAT browning and assist in preventing the development of obesity. However, how ILC2 in adipose tissue is regulated remains largely unknown. Here, our study shows that ILC2s are present in brown adipose tissue (BAT) as well as subcutaneous and epididymal WAT (sWAT and eWAT). The fractions of ILC2s, natural killer T (NKT) cells and eosinophils in sWAT, eWAT and BAT are significantly decreased by high-fat-diet (HFD) feeding and leptin deficiency-induced obesity. Consistent with this, the adipose expression and circulating levels of IL-33, a key inducing cytokine of ILC2, are significantly downregulated by obesity. Furthermore, administration of IL-33 markedly increases the fraction of ILC2 and eosinophil as well as the expression of UCP1 and tyrosine hydroxylase (TH), a rate-limiting enzyme in catecholamine biosynthesis, in adipose tissue of HFD-fed mice. On the other hand, cold exposure induces the expression levels of IL-33 and UCP1 and the population of ILC2 and eosinophil in sWAT, and these promoting effects of cold stress are reversed by neutralization of IL-33 signaling in vivo Moreover, the basal and cold-induced IL-33 and ILC2/eosinophil pathways are significantly suppressed by sympathetic denervation via local injection of 6-hydroxydopamine (6-OHDA) in sWAT. Taken together, our data suggest that the ILC2/eosinophil axis in adipose tissue is regulated by sympathetic nervous system and obesity in IL-33-dependent manner, and IL-33-driven ILC2/eosinophil axis is implicated in the development of obesity. 10.1530/JOE-16-0229
    Antigen- and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Kolodin Dmitriy,van Panhuys Nicolas,Li Chaoran,Magnuson Angela M,Cipolletta Daniela,Miller Christine M,Wagers Amy,Germain Ronald N,Benoist Christophe,Mathis Diane Cell metabolism A unique population of Foxp3(+)CD4(+) regulatory T (Treg) cells, with a distinct transcriptome and antigen-receptor repertoire, resides in visceral adipose tissue (VAT) of lean individuals. These cells regulate local inflammation and both local and systemic metabolic indices. Here we focus on expansion of the VAT Treg compartment in aging lean mice-assessing these cells' phenotypic conversion from conventional CD4(+) T cells, influx from lymphoid organs, and local population dynamics. Our findings establish that the VAT Treg compartment is seeded from thymocytes generated during the first weeks of life and expands beyond 10 weeks of age due to indolent proliferation, of certain clones in particular, coupled with enhanced survival. Accumulation of VAT Tregs depends on the antigen(s) presented by MHC class-II molecules and soluble mediators, notably interleukin(IL)-33. Addressing such factors therapeutically promises novel approaches for harnessing Tregs to stem the growing epidemic of obesity and consequent metabolic abnormalities. 10.1016/j.cmet.2015.03.005
    Sex-specific adipose tissue imprinting of regulatory T cells. Vasanthakumar Ajithkumar,Chisanga David,Blume Jonas,Gloury Renee,Britt Kara,Henstridge Darren C,Zhan Yifan,Torres Santiago Valle,Liene Sebastian,Collins Nicholas,Cao Enyuan,Sidwell Tom,Li Chaoran,Spallanzani Raul German,Liao Yang,Beavis Paul A,Gebhardt Thomas,Trevaskis Natalie,Nutt Stephen L,Zajac Jeffrey D,Davey Rachel A,Febbraio Mark A,Mathis Diane,Shi Wei,Kallies Axel Nature Adipose tissue is an energy store and a dynamic endocrine organ. In particular, visceral adipose tissue (VAT) is critical for the regulation of systemic metabolism. Impaired VAT function-for example, in obesity-is associated with insulin resistance and type 2 diabetes. Regulatory T (T) cells that express the transcription factor FOXP3 are critical for limiting immune responses and suppressing tissue inflammation, including in the VAT. Here we uncover pronounced sexual dimorphism in T cells in the VAT. Male VAT was enriched for T cells compared with female VAT, and T cells from male VAT were markedly different from their female counterparts in phenotype, transcriptional landscape and chromatin accessibility. Heightened inflammation in the male VAT facilitated the recruitment of T cells via the CCL2-CCR2 axis. Androgen regulated the differentiation of a unique IL-33-producing stromal cell population specific to the male VAT, which paralleled the local expansion of T cells. Sex hormones also regulated VAT inflammation, which shaped the transcriptional landscape of VAT-resident T cells in a BLIMP1 transcription factor-dependent manner. Overall, we find that sex-specific differences in T cells from VAT are determined by the tissue niche in a sex-hormone-dependent manner to limit adipose tissue inflammation. 10.1038/s41586-020-2040-3
    Potential of IL-33 for Preventing the Kidney Injury via Regulating the Lipid Metabolism in Gout Patients. Duan Lihua,Huang Yan,Su Qun,Lin Qingyan,Liu Wen,Luo Jiao,Yu Bing,He Yan,Qian Hongyan,Liu Yuan,Chen Jie,Shi Guixiu Journal of diabetes research Interleukin-33 (IL-33), the most recently discovered member of the IL-1 superfamily, has been linked to several human pathologies including autoimmune diseases, sepsis, and allergy through its specific IL-1 receptor ST2. However, there is little information regarding the role of IL-33 in gout. In this study, we investigated the potential role of IL-33 in gout patients. The serum level of IL-33 was measured by ELISA, and the clinical and laboratory parameters, serum creatinine, urea, and lipid, were extracted from medical record system. The serum IL-33 expression was predominantly increased in gout patients compared to healthy controls, and the IL-33 levels were higher in patients without kidney injury. Furthermore, IL-33 showed a negative correlation with biomarkers of kidney injury, such as CRE and urea. The lipid metabolism dysfunction, tophi, and hypertension are the common reasons for kidney injury in gout. Interestingly, inverse and positive correlation of IL-33 expression was observed in LDL and HDL, respectively. However, there was no significant alteration in the gout patients with hypertension and tophi. These data suggested that IL-33 might act as a protective role in kidney injury through regulating the lipid metabolism in gout. 10.1155/2016/1028401
    The modern interleukin-1 superfamily: Divergent roles in obesity. Lee Man K S,Yvan-Charvet Laurent,Masters Seth L,Murphy Andrew J Seminars in immunology Obesity is now recognised as a chronic, low-grade inflammatory disease contributing to insulin resistance, type 2 diabetes (T2D) and cardiovascular disease (CVD). Multiple mechanisms leading to the low grade inflammation in this setting have been suggested. Due to the complexity and interconnection of inflammatory and metabolic responses, there also remains a need to fully elucidate the inflammatory mechanisms that control obesity and associated metabolic disorders. One important avenue in the field that has gained great attention is the interleukin (IL)-1 superfamily of cytokines that consist of IL-1β, IL-18 and IL-33. IL-1β is well known for its contribution as an inflammatory mediator in obesity contributing to insulin resistance and T2D, whereas the IL-18 and IL-33 cytokines have been shown to oppose metabolic dysregulation. This review will focus on the current understanding of the IL-1 superfamily of cytokines in the setting of obesity and discuss how endogenous feedback loops can be exploited for therapeutic approaches to fight obesity and subsequent cardiometabolic disorders. 10.1016/j.smim.2016.10.001
    The NLRP3 Inflammasome and Its Role in T1DM. Sun Xiaoxiao,Pang Haipeng,Li Jiaqi,Luo Shuoming,Huang Gan,Li Xia,Xie Zhiguo,Zhou Zhiguang Frontiers in immunology The NLRP3 (nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome is a protein complex expressed in cells. It detects danger signals and induces the production of active caspase-1 and the maturation and release of IL (interleukin)-33, IL-18, IL-1β and other cytokines. T1DM (type 1 diabetes mellitus) is defined as a chronic autoimmune disorder characterized by the autoreactive T cell-mediated elimination of insulin-positive pancreatic beta-cells. Although the exact underlying mechanisms are obscure, researchers have proposed that both environmental and genetic factors are involved in the pathogenesis of T1DM. Furthermore, immune responses, including innate and adaptive immunity, play an important role in this process. Recently, the NLRP3 inflammasome, a critical component of innate immunity, was reported to be associated with T1DM. Here, we review the assembly and function of the NLRP3 inflammasome. In addition, the activation and regulatory mechanisms that enhance or attenuate NLRP3 inflammasome activation are discussed. Finally, we focus on the relationship between the NLRP3 inflammasome and T1DM, as well as its potential value for clinical use. 10.3389/fimmu.2020.01595
    Adventitial Stromal Cells Define Group 2 Innate Lymphoid Cell Tissue Niches. Dahlgren Madelene W,Jones Stephen W,Cautivo Kelly M,Dubinin Alexandra,Ortiz-Carpena Jorge F,Farhat Sepideh,Yu Kevin S,Lee Katharine,Wang Chaoqun,Molofsky Anna V,Tward Aaron D,Krummel Matthew F,Peng Tien,Molofsky Ari B Immunity Type 2 lymphocytes promote both physiologic tissue remodeling and allergic pathology, yet their physical tissue niches are poorly described. Here, we used quantitative imaging to define the tissue niches of group 2 innate lymphoid cells (ILC2s), which are critical instigators of type 2 immunity. We identified a dominant adventitial niche around lung bronchi and larger vessels in multiple tissues, where ILC2s localized with subsets of dendritic and regulatory T cells. However, ILC2s were most intimately associated with adventitial stromal cells (ASCs), a mesenchymal fibroblast-like subset that expresses interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP). In vitro, ASCs produced TSLP that supported ILC2 accumulation and activation. ILC2s and IL-13 drove reciprocal ASC expansion and IL-33 expression. During helminth infection, ASC depletion impaired lung ILC2 and Th2 cell accumulation and function, which are in part dependent on ASC-derived IL-33. These data indicate that adventitial niches are conserved sites where ASCs regulate type 2 lymphocyte expansion and function. 10.1016/j.immuni.2019.02.002
    Increased IL-12 and decreased IL-33 serum levels are associated with increased Th1 and suppressed Th2 cytokine profile in patients with diabetic nephropathy (CURES-134). Anand Gowrishankar,Vasanthakumar Rathinam,Mohan Vishwanathan,Babu Subash,Aravindhan Vivekanandhan International journal of clinical and experimental pathology The role played by recently discovered novel cytokine IL-33 in controlling T-helper (Th)1 and Th2 cytokines under conditions of diabetic nephropathy (DN) is less well studied. In the present study, we estimated the levels of IL-33 along with both Th1 and Th2 cytokines in the serum of normal glucose tolerant (NGT), diabetic subjects with (DN) or without nephropathy (DM) and correlated it with the clinical risk factors of diabetes and nephropathy. 222 study subjects were recruited from the Chennai Urban Rural Epidemiology Study (CURES): 61 NGT, 79 DM and 82 DN. IL-33 level was estimated by ELISA while other Th1 (IL-12, IFN-gamma and IL-2) and Th2 (IL-4, IL-5 and IL-13) cytokines were measured using a Bio-plex bead assay. DM subjects showed a mixed Th1-Th2 profile (increased IFN-g, IL-12, IL-4 and IL-13 and decreased IL-33) while DN subjects showed enhanced Th1 profile (increased IFN-g, IL-2 and IL-12) with suppression of Th2 cytokine (decreased IL-33 and IL-13). The IL-33 levels showed a serial decline with increasing severity of insulin resistance and microalbuminuria. DN was associated with enhanced Th1 response and suppression of Th2 responses which might be due to inreased levels of IL-12 and decreased levels of IL-33 cytokines respectively.
    Soluble ST2 is a biomarker for cardiovascular mortality related to abnormal glucose metabolism in high-risk subjects. Cardellini Marina,Rizza Stefano,Casagrande Viviana,Cardolini Iris,Ballanti Marta,Davato Francesca,Porzio Ottavia,Canale Maria Paola,Legramante Jacopo Maria,Mavilio Maria,Menghini Rossella,Martelli Eugenio,Farcomeni Alessio,Federici Massimo Acta diabetologica AIMS:Inflammation plays a role in the development and progression of type 2 diabetes macroangiopathy. Interleukin 33 (IL-33) drives production of Th2-associated cytokines. The soluble form of suppression of tumorigenicity 2 (sST2) acting as a decoy receptor blocks IL-33 and tones down Th2 inflammatory response. We investigated the role of sST2 as a predictor of CV and all-cause mortality in a cohort of patients affected by established atherosclerotic disease. METHODS:399 patients with atherosclerotic disease from the Tor Vergata Atherosclerosis Registry performed follow-up every year by phone interview. The primary endpoint was cardiovascular death and the secondary endpoint was death for any other disease. RESULTS:sST2 plasma levels were significantly increased from normal glucose-tolerant patients to patients with history of type 2 diabetes (p < 0.00001). Levels of sST2 were significantly correlated with fasting plasma glucose (R = 0.16, p = 0.002), HbA1c (R = 0.17, p = 0.002), and HOMA (R = 0.16, p = 0.004). Dividing patients in tertiles of sST2 levels, those belonging to the highest tertile showed an increased rate of all-cause and cardiovascular mortality, (all-cause mortality p = 0.045 and CVD mortality p = 0.02). A multivariate Cox analysis revealed that sST2 increased the risk in cardiovascular mortality per SD by hazard ratio 1.050 (95% CI 1.006-1.097, p = 0.025) after adjustment for age and hs-CRP while it did not significantly change the risk for all-cause mortality. CONCLUSIONS:High circulating level of sST2 is associated to increased CVD mortality and markers of metabolic dysfunction in subjects with atherosclerotic disease. 10.1007/s00592-018-1230-z
    Growth Differentiation Factor 15 Mediates Systemic Glucose Regulatory Action of T-Helper Type 2 Cytokines. Lee Seong Eun,Kang Seul Gi,Choi Min Jeong,Jung Saet-Byel,Ryu Min Jeong,Chung Hyo Kyun,Chang Joon Young,Kim Yong Kyung,Lee Ju Hee,Kim Koon Soon,Kim Hyun Jin,Lee Heung Kyu,Yi Hyon-Seung,Shong Minho Diabetes T-helper type 2 (Th2) cytokines, including interleukin (IL)-13 and IL-4, produced in adipose tissue, are critical regulators of intra-adipose and systemic lipid and glucose metabolism. Furthermore, IL-13 is a potential therapy for insulin resistance in obese mouse models. Here, we examined mediators produced by adipocytes that are responsible for regulating systemic glucose homeostasis in response to Th2 cytokines. We used RNA sequencing data analysis of cultured adipocytes to screen factors secreted in response to recombinant IL-13. Recombinant IL-13 induced expression of growth differentiation factor 15 (GDF15) via the Janus kinase-activated STAT6 pathway. In vivo administration of α-galactosylceramide or IL-33 increased IL-4 and IL-13 production, thereby increasing GDF15 levels in adipose tissue and in plasma of mice; however, these responses were abrogated in STAT6 knockout mice. Moreover, administration of recombinant IL-13 to wild-type mice fed a high-fat diet (HFD) improved glucose intolerance; this was not the case for GDF15 knockout mice fed the HFD. Taken together, these data suggest that GDF15 is required for IL-13-induced improvement of glucose intolerance in mice fed an HFD. Thus, beneficial effects of Th2 cytokines on systemic glucose metabolism and insulin sensitivity are mediated by GDF15. These findings open up a potential pharmacological route for reversing insulin resistance associated with obesity. 10.2337/db17-0333
    Glucagon-like peptide 1 signaling inhibits allergen-induced lung IL-33 release and reduces group 2 innate lymphoid cell cytokine production in vivo. Toki Shinji,Goleniewska Kasia,Reiss Sara,Zhang Jian,Bloodworth Melissa H,Stier Matthew T,Zhou Weisong,Newcomb Dawn C,Ware Lorraine B,Stanwood Gregg D,Galli Aurelio,Boyd Kelli L,Niswender Kevin D,Peebles R Stokes The Journal of allergy and clinical immunology BACKGROUND:IL-33 is one of the most consistently associated gene candidates for asthma identified by using a genome-wide association study. Studies in mice and in human cells have confirmed the importance of IL-33 in inducing type 2 cytokine production from both group 2 innate lymphoid cells (ILC2s) and T2 cells. However, there are no pharmacologic agents known to inhibit IL-33 release from airway cells. OBJECTIVE:We sought to determine the effect of glucagon-like peptide 1 receptor (GLP-1R) signaling on aeroallergen-induced airway IL-33 production and release and on innate type 2 airway inflammation. METHODS:BALB/c mice were challenged intranasally with Alternaria extract for 4 consecutive days. GLP-1R agonist or vehicle was administered starting either 2 days before the first Alternaria extract challenge or 1 day after the first Alternaria extract challenge. RESULTS:GLP-1R agonist treatment starting 2 days before the first Alternaria extract challenge decreased IL-33 release in the bronchoalveolar lavage fluid and dual oxidase 1 (Duox1) mRNA expression 1 hour after the first Alternaria extract challenge and IL-33 expression in lung epithelial cells 24 hours after the last Alternaria extract challenge. Furthermore, GLP-1R agonist significantly decreased the number of ILC2s expressing IL-5 and IL-13, lung protein expression of type 2 cytokines and chemokines, the number of perivascular eosinophils, mucus production, and airway responsiveness compared with vehicle treatment. GLP-1R agonist treatment starting 1 day after the first Alternaria extract challenge also significantly decreased eosinophilia and type 2 cytokine and chemokine expression in the airway after 4 days of Alternaria extract challenge. CONCLUSION:These results reveal that GLP-1R signaling might be a therapy to reduce IL-33 release and inhibit the ILC2 response to protease-containing aeroallergens, such as Alternaria. 10.1016/j.jaci.2017.11.043
    The Skinny: Pancreatic ILC2s Promote Insulin Secretion. Cautivo Kelly M,Molofsky Ari B Immunity Regulation of pancreatic insulin production is pivotal in the pathophysiology and treatment of diabetes. In this issue of Immunity, Dalmas et al. (2017) describe a type 2 immune circuit where pancreatic interleukin-33 (IL-33) promotes insulin secretion via the activity of islet-associated group 2 innate lymphoid cells (ILC2s). 10.1016/j.immuni.2017.11.004
    Relationships between epicardial adipose tissue thickness and adipo-fibrokine indicator profiles post-myocardial infarction. Gruzdeva Olga,Uchasova Evgenya,Dyleva Yulia,Borodkina Daria,Akbasheva Olga,Belik Ekaterina,Karetnikova Viktoria,Brel Natalia,Kokov Alexander,Kashtalap Vasiliy,Barbarash Olga Cardiovascular diabetology BACKGROUND:Determination of the impact of visceral obesity and epicardial adipose tissue thickness on stimulating growth factor levels during hospitalization for myocardial infarction is of potential importance for predicting outcomes and assessing the development of cardiofibrotic changes associated with maladaptive myocardial remodeling. In this study, we aimed to investigate the relationships between epicardial adipose tissue thickness, adipokine profiles, and the stimulating growth factor 2/interleukin-33 signaling system during hospitalization for myocardial infarction, and with the cardiac fibrosis extent 1-year post-MI in patients with visceral obesity. METHODS:Eighty-eight patients with myocardial infarction were grouped based on their visceral obesity. Serum leptin, adiponectin, stimulating growth factor 2, and interleukin-33 levels were measured on days 1 and 12 and at 1 year. The epicardial adipose tissue widths and the cardiac fibrosis areas were measured on day 12 and at 1 year. RESULTS:Visceral obesity was associated with epicardial adipose tissue thickness increases, adipokine imbalances, elevated leptin levels, and lower adiponectin levels during early hospitalization, and cardiac fibrosis development. Patients without visceral obesity had higher interleukin-33 and stimulating growth factor 2 levels during early hospitalization and lower cardiac fibrosis rates. Epicardial adipose tissue thickness was positively associated with cardiac fibrosis prevalence and interleukin-33 levels and negatively associated with stimulating growth factor 2 levels. The cardiac fibrosis extent was negatively associated with interleukin-33 levels and positively associated with stimulating growth factor 2 levels. CONCLUSIONS:Increases in epicardial adipose tissue thickness are associated with cardiac fibrosis development 1-year post-myocardial infarction and are higher in patients with visceral obesity. The metabolic activity of the epicardial adipose tissue is associated with elevated interleukin-33 and reduced stimulating growth factor 2 levels. 10.1186/s12933-018-0679-y
    Circulating levels of IL-33 are elevated by obesity and positively correlated with metabolic disorders in Chinese adults. Tang Haoneng,Liu Ning,Feng Xiaojing,Yang Yanyi,Fang Yiyuan,Zhuang Siqi,Dai Yufeng,Liu Meilian,Tang Lingli Journal of translational medicine BACKGROUND:Interleukin-33 (IL-33) plays a pivotal role in regulating innate immune response and metabolic homeostasis. However, whether its circulating level is correlated with obesity and metabolic disorders in humans remains largely unknown. We aimed to address this gap by determining IL-33 serum level and its downstream type 2 inflammatory cytokines interleukin-5 (IL-5) and interleukin-13 (IL-13) in overweight/obese population, and analyzing the specific associations between IL-33 and obesity metabolic phenotypes. METHODS:217 subjects were enrolled and divided into three groups: healthy control (HC) subjects, metabolically healthy overweight/obese (MHOO) subjects and metabolically unhealthy overweight/obese (MUOO) subjects. Circulating levels of IL-33, IL-5 and IL-13 were measured using ELISA analyses. Multivariate regression analyses were further performed to determine the independent association between IL-33 and obesity metabolic phenotypes. RESULTS:Circulating levels of IL-33 were significantly elevated in subjects of MUOO group compared with HC group and MHOO group, while no significant difference was observed between the latter two groups in IL-33 levels. Consistent with this, serum levels of IL-5/13 were higher in the MUOO group compared with HC and MHOO groups. After adjusted for all confounders, MUOO phenotype was significantly associated with increased IL-33 serum levels (OR = 1.70; 95% CI 1.09-2.64; p = 0.019). With the MHOO group as the reference population, higher circulating level of IL-33 was also positively associated with MUOO phenotype after adjusting for confounders (OR = 1.50; 95% CI 1.20-1.88; p = 2.91E-4). However, there was no significant association between MHOO phenotype and IL-33 levels (p = 0.942). Trend analysis further confirmed the positive correlation between MUOO phenotype and IL-33 level (p for trend = 0.019). Additionally, IL-33 was significantly and positively correlated with diastolic blood pressure (DBP), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), white blood cell (WBC), neutrophil and IL-5 only in MUOO group, while inversely correlated with high density lipoprotein cholesterol (HDL-C) in MHOO subjects. CONCLUSION:Circulating levels of IL-33 were significantly elevated in overweight/obese Chinese adults with metabolic disorders. Increased levels of IL-33 were positively associated with metabolically unhealthy overweight/obese phenotype and several metabolic syndrome risk factors. 10.1186/s12967-021-02711-x
    Galectin-3 and IL-33/ST2 axis roles and interplay in diet-induced steatohepatitis. Pejnovic Nada,Jeftic Ilija,Jovicic Nemanja,Arsenijevic Nebojsa,Lukic Miodrag L World journal of gastroenterology Immune reactivity and chronic low-grade inflammation (metaflammation) play an important role in the pathogenesis of obesity-associated metabolic disorders, including type 2 diabetes and nonalcoholic fatty liver disease (NAFLD), a spectrum of diseases that include liver steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Increased adiposity and insulin resistance contribute to the progression from hepatic steatosis to NASH and fibrosis through the development of proinflammatory and profibrotic processes in the liver, including increased hepatic infiltration of innate and adaptive immune cells, altered balance of cytokines and chemokines, increased reactive oxygen species generation and hepatocellular death. Experimental models of dietary-induced NAFLD/NASH in mice on different genetic backgrounds or knockout mice with different immune reactivity are used for elucidating the pathogenesis of NASH and liver fibrosis. Galectin-3 (Gal-3), a unique chimera-type β-galactoside-binding protein of the galectin family has a regulatory role in immunometabolism and fibrogenesis. Mice deficient in Gal-3 develop pronounced adiposity, hyperglycemia and hepatic steatosis, as well as attenuated liver inflammation and fibrosis when fed an obesogenic high-fat diet. Interleukin (IL)-33, a member of the IL-1 cytokine family, mediates its effects through the ST receptor, which is present on immune and nonimmune cells and participates in immunometabolic and fibrotic disorders. Recent evidence, including our own data, suggests a protective role for the IL-33/IL-33R (ST2) signaling pathway in obesity, adipose tissue inflammation and atherosclerosis, but a profibrotic role in NASH development. The link between Gal-3 and soluble ST2 in myocardial fibrosis and heart failure progression has been demonstrated and we have recently shown that Gal-3 and the IL-33/ST2 pathway interact and both have a profibrotic role in diet-induced NASH. This review discusses the current evidence on the roles of Gal-3 and the IL-33/ST2 pathway and their interplay in obesity-associated hepatic inflammation and fibrogenesis that may be of interest in the development of therapeutic interventions to prevent and/or reverse obesity-associated hepatic inflammation and fibrosis. 10.3748/wjg.v22.i44.9706
    Correlation Profile of Suppression of Tumorigenicity 2 and/or Interleukin-33 with Biomarkers in the Adipose Tissue of Individuals with Different Metabolic States. Hasan Amal,Kochumon Shihab,Al-Ozairi Ebaa,Tuomilehto Jaakko,Al-Mulla Fahd,Ahmad Rasheed Diabetes, metabolic syndrome and obesity : targets and therapy Purpose:The suppression of tumorigenicity 2 (ST2) has two main splice variants including a membrane bound (ST2) form, which activates the myeloid differentiation primary response 88 (MyD88)/nuclear factor-kappa B (NF-κB) signaling pathway, and a secreted soluble form (sST2), which acts as a decoy receptor for ST2 ligand, interleukin (IL)-33. The IL-33/ST2 axis is protective against obesity, insulin resistance, and type 2 diabetes (T2D). In humans, adipose tissue IL-33 displays distinct correlation profiles with glycated hemoglobin, ST2, and other immunometabolic mediators, depending on the glycemic health of the individuals. We determined whether adipose tissue ST2 displays distinct correlation profiles with immunometabolic mediators and whether ST2 and/or IL-33 are correlated with intracellular signaling molecules. Patients and Methods:A total of 91 adults with normal glycemia, prediabetes, and T2D were included. After measuring their anthropometric and biochemical parameters, subcutaneous adipose tissues were isolated and mRNA expression of biomarkers was measured. Results:In individuals with normal glycemia, adipose tissue ST2 was directly correlated with chemokine (C-C motif) ligand (CCL)-2, CCL5, IL-12, fibrinogen-like protein 2 (FGL2) and interferon regulatory factor (IRF)-4, but inversely correlated with cytochrome C oxidase subunit 7A1. IL-33 and ST2 were directly correlated with tumor necrosis factor receptor-associated factor 6 (TRAF6), NF-κB, and nuclear factor of activated T-cells 5 (NFAT5). In individuals with prediabetes, ST2 was inversely correlated with IL-5, whereas IL-33 but not ST2 was directly correlated with MyD88 and NF-κB. In individuals with T2D, ST2 was directly correlated with CCL2, IL-1β, and IRF5. IL-33 and ST2 were directly correlated with MyD88, TRAF6, and NF-κB. Conclusion:Adipose tissue ST2 and IL-33 show different correlation profiles with various immunometabolic biomarkers depending on the metabolic state of the individuals. Therefore, targeting the IL-33/ST2 axis might form the basis for novel therapies to combat metabolic disorders. 10.2147/DMSO.S251978
    Ageing is associated with molecular signatures of inflammation and type 2 diabetes in rat pancreatic islets. Sandovici Ionel,Hammerle Constanze M,Cooper Wendy N,Smith Noel H,Tarry-Adkins Jane L,Dunmore Benjamin J,Bauer Julien,Andrews Simon R,Yeo Giles S H,Ozanne Susan E,Constância Miguel Diabetologia AIMS/HYPOTHESIS:Ageing is a major risk factor for development of metabolic diseases such as type 2 diabetes. Identification of the mechanisms underlying this association could help to elucidate the relationship between age-associated progressive loss of metabolic health and development of type 2 diabetes. We aimed to determine molecular signatures during ageing in the endocrine pancreas. METHODS:Global gene transcription was measured in pancreatic islets isolated from young and old rats by Ilumina BeadChip arrays. Promoter DNA methylation was measured by Sequenom MassArray in 46 genes that showed differential expression with age, and correlations with expression were established. Alterations in morphological and cellular processes with age were determined by immunohistochemical methods. RESULTS:Age-related changes in gene expression were found at 623 loci (>1.5-fold, false discovery rate [FDR] <5%), with a significant (FDR < 0.05) enrichment in genes previously implicated in islet-cell function (Enpp1, Abcc8), type 2 diabetes (Tspan8, Kcnq1), inflammatory processes (Cxcl9, Il33) and extracellular matrix organisation (Col3a1, Dpt). Age-associated transcriptional differences negatively correlated with promoter DNA methylation at several loci related to inflammation, glucose homeostasis, cell proliferation and cell-matrix interactions (Il33, Cxcl9, Gpr119, Fbp2, Col3a1, Dpt, Spp1). CONCLUSIONS/INTERPRETATION:Our findings suggest that a significant proportion of pancreatic islets develop a low-grade 'chronic' inflammatory status with ageing and this may trigger altered functional plasticity. Furthermore, we identified changes in expression of genes previously linked to type 2 diabetes and associated changes in DNA methylation that could explain their age-associated dysregulation. These findings provide new insights into key (epi)genetic signatures of the ageing process in islets. 10.1007/s00125-015-3837-8
    IL-33 is negatively associated with the BMI and confers a protective lipid/metabolic profile in non-diabetic but not diabetic subjects. Hasan Amal,Al-Ghimlas Fahad,Warsame Samia,Al-Hubail Asma,Ahmad Rasheed,Bennakhi Abdullah,Al-Arouj Monira,Behbehani Kazem,Dehbi Mohammed,Dermime Said BMC immunology OBJECTIVE:Recent studies have demonstrated a protective role for IL-33 against obesity-associated inflammation, atherosclerosis and metabolic abnormalities. IL-33 promotes the production of T helper type 2 (Th2) cytokines, polarizes macrophages towards a protective alternatively activated phenotype, reduces lipid storage and decreases the expression of genes associated with lipid metabolism and adipogenesis. Our objective was to determine the level of serum IL-33 in non-diabetic and diabetic subjects, and to correlate these levels with clinical (BMI and body weight) and metabolic (serum lipids and HbA1c) parameters. METHODS:The level of IL-33 was measured in the serum of lean, overweight and obese non-diabetic and diabetic subjects, and then correlated with clinical and metabolic parameters. RESULTS:Non-lean subjects had significantly (P = 0.01) lower levels of IL-33 compared to lean controls. IL-33 was negatively correlated with the BMI and body weight in lean and overweight, but not obese (non-diabetic and diabetic), subjects. IL-33 is associated with protective lipid profiles, and is negatively correlated with HbA1c, in non-diabetic (lean, overweight and obese) but not diabetic subjects. CONCLUSIONS:Our data support previous findings showing a protective role for IL-33 against adiposity and atherosclerosis, and further suggest that reduced levels of IL-33 may put certain individuals at increased risk of developing atherosclerosis and insulin resistance. Therefore, IL-33 may serve as a novel marker to predict those who may be at increased risk of developing atherosclerosis. 10.1186/1471-2172-15-19
    IL-33 and ST2 levels in chronic kidney disease: Associations with inflammation, vascular abnormalities, cardiovascular events, and survival. Gungor Ozkan,Unal Hilmi Umut,Guclu Aydin,Gezer Mustafa,Eyileten Tayfun,Guzel Fatma Betül,Altunoren Orcun,Erken Ertugrul,Oguz Yusuf,Kocyigit Ismail,Yilmaz Mahmut Ilker PloS one OBJECTIVE:Increased inflammation, associated with the increase in chronic kidney disease (CKD) stage, has a very important influence in vascular injury and cardiovascular diseases. In this study, we aimed to investigate the levels of IL-33 and ST2 in the different stages of CKD and to determine their effect on vascular damage and cardiovascular events (CVE). METHODS:This was an observational cohort study in which serum IL-33 and ST2 were obtained from 238 CKD (stages 1-5) patients. We examined the changes in IL-33/ST2 levels in CKD patients, as well as the association with a surrogate of endothelial dysfunction. Fatal and non-fatal CVE were recorded for a mean of 24 months. We also performed a COX regression analysis to determine the association of IL-33/ST2 levels with CVE and survival. RESULTS:IL-33 and ST2 levels were significantly increased and estimated glomerular filtration rates (eGFR) were decreased. Flow-mediated dilatation (FMD) was significantly decreased from stage 1 to stage 5 CKD. IL-33 and ST2 levels were associated with FMD, and ST2 was a predictor. Multivariate Cox analysis showed that the presence of diabetes mellitus, smoking, and proteinuria and haemoglobin, Hs-CRP, IL-33, and ST2 were associated with the risk of CVE. Kaplan-Meier survival curves showed that patients with IL-33 and ST2 levels below the median value (IL-33 = 132.6 ng/L, ST2 = 382.9 pg/mL) had a higher cumulative survival compared with patients who had IL-33 and ST2 levels above the median value (log-rank test, p = 0.000). CONCLUSION:This is the first study that demonstrates that serum IL-33 and ST2 are associated with vascular injury, cardiovascular events, and survival in CKD patients. 10.1371/journal.pone.0178939
    IL-33/ST2 axis in inflammation and immunopathology. Milovanovic Marija,Volarevic Vladislav,Radosavljevic Gordana,Jovanovic Ivan,Pejnovic Nada,Arsenijevic Nebojsa,Lukic Miodrag L Immunologic research Interleukin-33 (IL-33), a member of the IL-1 family of cytokines, binds to its plasma membrane receptor, heterodimeric complex consisted of membrane-bound ST2L and IL-1R accessory protein, inducing NFkB and MAPK activation. IL-33 exists as a nuclear precursor and may act as an alarmin, when it is released after cell damage or as negative regulator of NFκB gene transcription, when acts in an intracrine manner. ST2L is expressed on several immune cells: Th2 lymphocytes, NK, NKT and mast cells and on cells of myeloid lineage: monocytes, dendritic cells and granulocytes. IL-33/ST2 axis can promote both Th1 and Th2 immune responses depending on the type of activated cell and microenvironment and cytokine network in damaged tissue. We previously described and discuss here the important role of IL-33/ST2 axis in experimental models of type 1 diabetes, experimental autoimmune encephalomyelitis, fulminant hepatitis and breast cancer. We found that ST2 deletion enhance the development of T cell-mediated autoimmune disorders, EAE and diabetes mellitus type I. Disease development was accompanied by dominantly Th1/Th17 immune response but also higher IL-33 production, which suggest that IL-33 in receptor independent manner could promote the development of inflammatory autoreactive T cells. IL-33/ST2 axis has protective role in Con A hepatitis. ST2-deficient mice had more severe hepatitis with higher influx of inflammatory cells in liver and dominant Th1/Th17 systemic response. Pretreatment of mice with IL-33 prevented Con A-induced liver damage through prevention of apoptosis of hepatocytes and Th2 amplification. Deletion of IL-33/ST2 axis enhances cytotoxicity of NK cells, production of IFN-γ in these cells and systemic production of IFN-γ, IL-17 and TNF-α, which leads to attenuated tumor growth. IL-33 treatment of tumor-bearing mice suppresses activity of NK cells, dendritic cell maturation and enhances alternative activation of macrophages. In conclusion, we observed that IL-33 has attenuated anti-inflammatory effects in T cell-mediated responses and that both IL-33 and ST2 could be further explored as potential therapeutic targets in treatment of immune-mediated diseases. 10.1007/s12026-012-8283-9
    IL-1 family members in the pathogenesis and treatment of metabolic disease: Focus on adipose tissue inflammation and insulin resistance. Ballak Dov B,Stienstra Rinke,Tack Cees J,Dinarello Charles A,van Diepen Janna A Cytokine Obesity is characterized by a chronic, low-grade inflammation that contributes to the development of insulin resistance and type 2 diabetes. Cytokines and chemokines produced by immunocompetent cells influence local as well as systemic inflammation and are therefore critical contributors to the pathogenesis of type 2 diabetes. Hence, cytokines that modulate inflammatory responses are emerging as potential targets for intervention and treatment of the metabolic consequences of obesity. The interleukin-1 (IL-1) family of cytokines and receptors are key mediators of innate inflammatory responses and exhibit both pro- and anti-inflammatory functions. During the last decades, mechanistic insights into how the IL-1 family affects the initiation and progression of obesity-induced insulin resistance have increased significantly. Here, we review the current knowledge and understanding, with emphasis on the therapeutic potential of individual members of the IL-1 family of cytokines for improving insulin sensitivity in patients with diabetes. 10.1016/j.cyto.2015.05.005
    Conflicting vascular and metabolic impact of the IL-33/sST2 axis. Altara Raffaele,Ghali Rana,Mallat Ziad,Cataliotti Alessandro,Booz George W,Zouein Fouad A Cardiovascular research Interleukin 33 (IL-33), which is expressed by several immune cell types, endothelial and epithelial cells, and fibroblasts, is a cytokine of the IL-1 family that acts both intra- and extracellularly to either enhance or resolve the inflammatory response. Intracellular IL-33 acts in the nucleus as a regulator of transcription. Once released from cells by mechanical stress, inflammatory cytokines, or necrosis, extracellular IL-33 is proteolytically processed to act in an autocrine/paracrine manner as an 'alarmin' on neighbouring or various immune cells expressing the ST2 receptor. Thus, IL-33 may serve an important role in tissue preservation and repair in response to injury; however, the actions of IL-33 are dampened by a soluble form of ST2 (sST2) that acts as a decoy receptor and is produced by endothelial and certain immune cells. Accumulating evidence supports the conclusion that sST2 is a biomarker of vascular health with diagnostic and/or prognostic value in various cardiovascular diseases, including coronary artery disease, myocardial infarction, atherosclerosis, giant-cell arteritis, acute aortic dissection, and ischaemic stroke, as well as obesity and diabetes. Although sST2 levels are positively associated with cardiovascular disease severity, the assumption that IL-33 is always beneficial is naïve. It is increasingly appreciated that the pathophysiological importance of IL-33 is highly dependent on cellular and temporal expression. Although IL-33 is atheroprotective and may prevent obesity and type 2 diabetes by regulating lipid metabolism, IL-33 appears to drive endothelial inflammation. Here, we review the current knowledge of the IL-33/ST2/sST2 signalling network and discuss its pathophysiological and translational implications in cardiovascular diseases. 10.1093/cvr/cvy166
    IL-33 improves wound healing through enhanced M2 macrophage polarization in diabetic mice. He Rongguo,Yin Hui,Yuan Baohong,Liu Tao,Luo Li,Huang Ping,Dai Liangcheng,Zeng Kang Molecular immunology IL-33 is a newly discovered member of the IL-1 family and has been identified as a potent inducer of Th2 type immunity. Emerging evidence imply that IL-33 may also act as an alarm to alert the immune system when released by epithelial barrier tissues during trauma or infection. In this study, we further investigate the potential efficacy of IL-33 on dermal wound healing in streptozotocin-induced diabetic mice. A full-thickness skin wound was generated on the back of diabetic mice and treated with IL-33 or vehicle topically. Our data showed that IL-33 delivery contributed to diabetic wound closure with wounds gaping narrower and exhibiting elevated re-epithelialization. IL-33 promoted the new extracellular matrix (ECM) deposition and angiogenesis formation, which indicates an important role of IL-33 on matrix synthesis and neovascularization. Meanwhile, IL-33 accelerated the development of M2 macrophages in wound sites in vivo, and amplified IL-13-induced polarization of bone marrow-derived macrophages toward a M2 phenotype in vitro. Furthermore, IL-33-amplified M2 macrophages augmented the proliferation of fibroblasts and ECM deposition. All together, these results strongly suggest manipulation of IL-33-mediated signal might be a potential therapeutic approach for diabetic skin wounds. 10.1016/j.molimm.2017.06.249
    Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation. Molofsky Ari B,Van Gool Frédéric,Liang Hong-Erh,Van Dyken Steven J,Nussbaum Jesse C,Lee Jinwoo,Bluestone Jeffrey A,Locksley Richard M Immunity Group 2 innate lymphoid cells (ILC2s) and regulatory T (Treg) cells are systemically induced by helminth infection but also sustain metabolic homeostasis in adipose tissue and contribute to tissue repair during injury. Here we show that interleukin-33 (IL-33) mediates activation of ILC2s and Treg cells in resting adipose tissue, but also after helminth infection or treatment with IL-2. Unexpectedly, ILC2-intrinsic IL-33 activation was required for Treg cell accumulation in vivo and was independent of ILC2 type 2 cytokines but partially dependent on direct co-stimulatory interactions via ICOSL-ICOS. IFN-γ inhibited ILC2 activation and Treg cell accumulation by IL-33 in infected tissue, as well as adipose tissue, where repression increased with aging and high-fat diet-induced obesity. IL-33 and ILC2s are central mediators of type 2 immune responses that promote tissue and metabolic homeostasis, and IFN-γ suppresses this pathway, likely to promote inflammatory responses and divert metabolic resources necessary to protect the host. 10.1016/j.immuni.2015.05.019
    Distinct immunocyte-promoting and adipocyte-generating stromal components coordinate adipose tissue immune and metabolic tenors. Spallanzani Raul German,Zemmour David,Xiao Tianli,Jayewickreme Teshika,Li Chaoran,Bryce Paul J,Benoist Christophe,Mathis Diane Science immunology Regulatory T cells (T) are key brakes on the visceral adipose tissue (VAT) inflammation that regulates local and systemic metabolic tenor. Breakdown of this regulation promotes type 2 diabetes. The cytokine IL-33 expands and sustains the unique T population residing within VAT. Here, relying on single-cell RNA sequencing, we identified the major IL-33 producers in VAT to be particular mesenchymal stromal cell subtypes, related to but distinct from adipocyte progenitor cells. We explored modulation of the VAT stromal cell landscape with physiologic variables such as age and sex, as well as its remodeling in pathogenic states like obesity. Last, we uncovered a VAT T:stromal cell negative regulatory loop that keeps the potent effect of IL-33 under rein. 10.1126/sciimmunol.aaw3658
    Interleukin-33-Activated Islet-Resident Innate Lymphoid Cells Promote Insulin Secretion through Myeloid Cell Retinoic Acid Production. Dalmas Elise,Lehmann Frank M,Dror Erez,Wueest Stephan,Thienel Constanze,Borsigova Marcela,Stawiski Marc,Traunecker Emmanuel,Lucchini Fabrizio C,Dapito Dianne H,Kallert Sandra M,Guigas Bruno,Pattou Francois,Kerr-Conte Julie,Maechler Pierre,Girard Jean-Philippe,Konrad Daniel,Wolfrum Christian,Böni-Schnetzler Marianne,Finke Daniela,Donath Marc Y Immunity Pancreatic-islet inflammation contributes to the failure of β cell insulin secretion during obesity and type 2 diabetes. However, little is known about the nature and function of resident immune cells in this context or in homeostasis. Here we show that interleukin (IL)-33 was produced by islet mesenchymal cells and enhanced by a diabetes milieu (glucose, IL-1β, and palmitate). IL-33 promoted β cell function through islet-resident group 2 innate lymphoid cells (ILC2s) that elicited retinoic acid (RA)-producing capacities in macrophages and dendritic cells via the secretion of IL-13 and colony-stimulating factor 2. In turn, local RA signaled to the β cells to increase insulin secretion. This IL-33-ILC2 axis was activated after acute β cell stress but was defective during chronic obesity. Accordingly, IL-33 injections rescued islet function in obese mice. Our findings provide evidence that an immunometabolic crosstalk between islet-derived IL-33, ILC2s, and myeloid cells fosters insulin secretion. 10.1016/j.immuni.2017.10.015
    IL-33/IL-33R in various types of carotid artery atherosclerotic lesions. Stankovic Milos,Ljujic Biljana,Babic Srdjan,Maravic-Stojkovic Vera,Mitrovic Slobodanka,Arsenijevic Nebojsa,Radak Djordje,Pejnovic Nada,Lukic Miodrag L Cytokine OBJECTIVE:Inflammation plays a crucial role in the progression of atherosclerotic plaques. The aim of the study was to investigate serum levels and expression of Interleukin-33 (IL-33) and ST2 receptor in atherosclerotic plaques and to analyze correlation with the type of the carotid plaques in patients with carotid disease. METHODS:This study included 191 consecutive patients submitted for carotid endarterectomy (CEA). Preoperative serum levels of IL-33 and soluble ST2 (sST2) were measured. Atherosclerotic plaques obtained during surgery were initially histologically classified and immunohistochemical analyzes of IL-33, IL-33R, CD68 and alpha-SMA expression was performed. Ultrasound assessment of the level of carotid stenosis in each patient was performed prior to carotid surgery. Demographic and clinical data such as gender, age, smoking status, blood pressure, glycaemia, hemoglobin and creatinine levels, and comorbidities were collected and the comparisons between variables were statistically evaluated. RESULTS:Serum levels of IL-33 (35.86 ± 7.93 pg/ml vs.12.29 ± 1.8 pg/ml, p < 0.05) and sST2 (183 ± 8.03 pg/ml vs. 122.31 ± 15.89 pg/ml, p < 0.05) were significantly higher in the group of CEA patients vs. healthy subjects. We demonstrated abundant tissue expression of IL-33 and ST2 in atherosclerotic carotid artery lesions. The levels of IL-33 and IL-33R expression were significantly higher in vulnerable plaques and significantly correlated with the degree of inflammatory cells infiltration in these plaques (R = 0.579, p = 0.049). Immunohistochemical analysis also revealed that cells responsible for IL-33 expression are not only mononuclear cells confined to inflammatory atherosclerotic lesions, but also smooth muscle cells which gained phenotypic characteristics of foam cells and were loaded with lipid droplets. CONCLUSION:The obtained results confirm the importance of IL-33/ST2 axis in the process of atherosclerosis, and indicate its ambiguous function in immune response, whether as proinflammatory cytokine in advanced atherosclerotic lesions, or as profibrotic, in early lesions. 10.1016/j.cyto.2019.05.010
    Elevated Circulating Interleukin 33 Levels in Stable Renal Transplant Recipients at High Risk for Cardiovascular Events. Mansell Holly,Soliman Mahmoud,Elmoselhi Hamdi,Shoker Ahmed PloS one BACKGROUND:The Major Adverse Cardiovascular Events calculator (CRCRTR-MACE) estimates the burden of cardiovascular risk in renal transplant recipients (RTR). Our recent study of 95 RTR reported the 7-year median risk of cardiovascular events (CVE) to be 9.97%, ranging from 1.93 to 84.27%. Nearly a third (28.4%) of the cohort was above 20% risk for a CVE. Since interleukins (ILs) as part of the inflammatory response may play a role in the pathogenesis of cardiovascular disease (CVD), we extended this study to identify which ILs are associated with high cardiovascular risk in this population. METHODS:Twenty-two ILs were measured by multiplexed fluorescent bead-based immunoassay in 95 RTR and 56 normal controls. Stepwise analysis after multivariate determination of significant demographic and inflammatory variables was performed between the high and low-CVD risk groups (which were arbitrarily set at scores <10% and ≥20%, respectively). Normalized data was presented as mean ± SD and non-normalized data as median (minimum-maximum). Significance was measured at <0.05. RESULTS:27.5% of the low-risk and 31.3% of the high-risk groups had mean IL levels above the 95 percentile of the normal control levels. In the non-parametric analysis IL-6, 9, 16, 17 and 33 were significantly higher in the high-risk group compared to the control. Univariate analysis (UVA) of the high-risk group identified IL-33 as the only IL that remained significantly higher than the control and low-risk groups (p = 0.000). The percentage of patients with IL-33 levels above the 90 percentile of control value in the low and high-risk groups were 15.6% and 52.0%, respectively (p<0.002). UVA of factors significant to high IL-33 levels included estimated glomerular filtration rate (eGFR), while diabetes mellitus, serum phosphorus, microalbuminuria and age also remained significant in the multivariate analysis. CONCLUSION:Circulating IL-33 level is positively associated with high CRCRTR-MACE score. Diminished eGFR, age, diabetes, serum phosphorus and microalbuminurea demonstrate significant relationship with elevated IL-33 levels, supporting the possible pathognomonic role of IL-33 in the cardiovascular burden in RTR. 10.1371/journal.pone.0142141
    [Biological role of Interleukin 33 and its importance in pathophysiology of cardiovascular system]. Czyzewska-Buczyńska Agnieszka,Zuk Natalia,Romanowska-Micherda Katarzyna,Witkiewicz Wojciech Postepy higieny i medycyny doswiadczalnej (Online) Interleukin 33 (IL-33) is a member of the IL-1 cytokin family. It is expressed by various cells and tissues, mainly epithelial and endothelial cells. It is a cytokine with dual function. It may act both as a traditional cytokine and as intracellular nuclear factor, functioning as transcription regulator. Its biological effect via interaction with membrane-bound ST2 receptor and IL-1 receptor accessory protein (IL-1RAcP) is associated with the induction of Th2-type immune response and IL-5 and IL-13 synthesis. IL-33 has a strong immunoregulatory properties. Depending on the type of activated cells, microenvironment, and costimulatory factors, IL-33 can act either as a pro- or anti-inflammatory cytokine. Recent studies indicate various protective effect of IL-33/ST2 sygnaling in atherosclerosis, obesity, disorders in glucose homeostasis and in heart diseases. The paper presents current state of knowledge about the structure and biological function of IL-33 and its receptor ST2, with particular emphasis on its role in pathophysiology of cardiovascular system. 10.5604/17322693.1109218
    The pro-inflammatory marker soluble suppression of tumorigenicity-2 (ST2) is reduced especially in diabetic morbidly obese patients undergoing bariatric surgery. Demyanets Svitlana,Kaun Christoph,Kaider Alexandra,Speidl Walter,Prager Manfred,Oravec Stanislav,Hohensinner Philipp,Wojta Johann,Rega-Kaun Gersina Cardiovascular diabetology BACKGROUND:High soluble suppression of tumorigenicity-2 (sST2) is a marker of poor prognosis in chronic inflammatory conditions. ST2 and its ligand interleukin (IL)-33 are elevated in adipose tissue of obese individuals. We aimed to evaluate circulating sST2 and IL-33 as possible markers of metabolic benefit in morbidly overweight patients after Roux-en-Y gastric bypass (RYGB) bariatric surgery. METHODS:sST2, IL-33, high sensitive IL-6, high sensitive C-reactive protein (hsCRP), leptin, cholesterol metabolism and liver parameters were measured in 80 morbidly obese individuals before and 1 year after bariatric surgery. RESULTS:sST2 was higher (P = 0.03) in diabetics as compared to individuals without diabetes. Baseline sST2 was also higher in males than in females (P= 0.0002). One year after bariatric surgery, sST2 levels were decreased (median 120, IQR 59-176 pg/mL) as compared to sST2 before surgery (median 141, IQR 111-181, P = 0.0024), and the diabetic group showed most pronounced reduction in sST2 (P = 0.0016). An association was found between sST2 and liver function parameters before and after bariatric surgery, and between baseline sST2 and total cholesterol, triglyceride, total low density lipoprotein (LDL), small dense LDL, Apolipoprotein B as well as with small dense high density lipoproteins (HDL). In the subgroup of diabetic patients positive correlation between IL-33 and sST2 (r = 0.44, P = 0.05) was noticed. CONCLUSIONS:Circulating sST2 is associated with markers of liver functions and lipid metabolism in severely obese patients and a reduction of sST2 was shown after successful bariatric surgery, most prominently in diabetic patients. 10.1186/s12933-020-01001-y
    IL-33 Effect on Quantitative Changes of CD4CD25FOXP3 Regulatory T Cells in Children with Type 1 Diabetes. Ryba-Stanisławowska Monika,Werner Paulina,Skrzypkowska Maria,Brandt Agnieszka,Myśliwska Jolanta Mediators of inflammation IL-33 is an IL-1 cytokine family member, with ability to induce both Th1 and Th2 immune responses. It binds to ST2 receptor, whose deficiency is associated with enhanced inflammatory response. The most recent studies have shown the immunoregulatory effect of IL-33 on Tregs in animal models. As type 1 diabetes is an autoimmune, inflammatory disease, where Treg defects have been described, we aimed to analyze the influence of recombinant IL-33 on quantitative properties of regulatory CD4CD25FOXP3 T cells. CD4CD25FOXP3 as well as CD4CD25FOXP3ST2 Tregs were analyzed by flow cytometry. In a group of patients with type 1 diabetes IL-33 treatment induced regulatory CD4CD25FOXP3 cell frequencies as well as upregulating the surface expression of ST2 molecule. In addition, the number of CD4CD25FOXP3 cells carrying ST2 receptor increased significantly. Similar effect was observed in case of the FOXP3 expression. We did not observe any significant changes in IL-33 treated cells of healthy controls. The level of ST2 was higher in serum of patients with type 1 diabetes in comparison to their healthy counterparts. We propose that IL-33 becomes an additional immunostimulatory factor used to induce Treg expansion in future clinical trials of adoptive therapy in type 1 diabetes. 10.1155/2016/9429760
    Association between Adipose Tissue Interleukin-33 and Immunometabolic Markers in Individuals with Varying Degrees of Glycemia. Hasan Amal,Kochumon Shihab,Al-Ozairi Ebaa,Tuomilehto Jaakko,Ahmad Rasheed Disease markers Introduction:Interleukin-33 (IL-33), the ligand for the receptor ST2, is abundant in adipose tissue, including preadipocytes, adipocytes, and endothelial cells. The IL-33/ST2 axis is protective against obesity, insulin resistance, and type 2 diabetes (T2D) in animal models. We determined whether adipose tissue IL-33 was associated with glycated hemoglobin (HbA1c), as well as mediators of inflammation and immune regulation and beiging of adipose tissue, among individuals with varying degrees of glycemia. Materials and Methods:A total of 91 adults with normoglycemia, prediabetes, and T2D were included. After measuring their anthropometric and biochemical parameters, subcutaneous adipose tissue samples were isolated and mRNA expression of cytokines, chemokines, chemokine receptors, pattern recognition receptors, and mediators involved in beiging of adipose tissue were measured. Results:Adipose tissue IL-33 was inversely associated with HbA1c in individuals with normoglycemia and T2D but not in those with prediabetes and was inversely correlated with fasting plasma glucose in individuals with T2D and with a better glycemic control. IL-33-to-ST2 ratio was inversely correlated with HbA1c in individuals with normoglycemia but not in those with prediabetes or T2D. IL-33 was directly associated with ST2, CD302, fibrinogen-like protein 2 (FGL2), and PR domain containing 16 (PRDM16) but inversely correlated with chemokine (C-C motif) ligand (CCL) 7 and CCL8 in individuals with normoglycemia. Similarly, IL-33 was directly associated with ST2, CD302, FGL2, PRDM16, and, additionally, toll-like receptor (TLR) 3 and IL-12A in individuals with T2D. However, IL-33 was not associated with any of these mediators but was directly and strongly associated with TLR9 in individuals with prediabetes. Conclusions:IL-33 and/or IL-33/ST2 dynamics and biological functions may play a role in overall glycemia among humans and may represent a novel target by which glucose-lowering managements confer their beneficial effects. 10.1155/2019/7901062
    Effector and regulatory T cell subsets in diabetes-associated inflammation. Is there a connection with ST2/IL-33 axis? Perspective. Ryba-Stanisławowska Monika,Stanisławowski Marcin,Myśliwska Jolanta Autoimmunity Type 1 diabetes (DM1) is a chronic inflammatory disease, which when progresses leads to the development of late vascular complications. The disease involves impairments in regulatory and effector subsets of T lymphocytes, which suppress and maintain inflammatory response, respectively. ST2/IL-33 pathway is involved in T-cell-mediated immune response and might regulate the inflammatory process in several diseases. This review presents the latest research findings regarding effector and regulatory T cell subsets in the context of inflammation accompanying DM1 with particular focus on the ST2/IL-33 network and its possible association with T cell-mediated immunity. 10.3109/08916934.2014.886198
    Severe obesity increases adipose tissue expression of interleukin-33 and its receptor ST2, both predominantly detectable in endothelial cells of human adipose tissue. Zeyda M,Wernly B,Demyanets S,Kaun C,Hämmerle M,Hantusch B,Schranz M,Neuhofer A,Itariu B K,Keck M,Prager G,Wojta J,Stulnig T M International journal of obesity (2005) OBJECTIVE:Obesity is associated with chronic inflammation of the adipose tissue, which contributes to obesity-associated complications such as insulin resistance and type 2 diabetes. Interleukin (IL)-33 acts via its receptor ST2 and is involved in the pathogenesis of inflammatory disorders including atherosclerosis and heart disease. IL-33 has been demonstrated to promote endothelial cell inflammatory response, but also anti-inflammatory and protective actions such as TH2 and M2 polarization of T cells and macrophages, respectively. IL-33 and ST2 have been shown to be expressed in human and murine adipose tissue. Our objective was to investigate alterations in obesity and a possible role of IL-33 in adipose tissue inflammation. SUBJECTS AND METHODS:We investigated severely obese patients (BMI>40 kg m(-2), n=20) and lean to overweight controls (BMI<30 kg m(-2); n=20) matched for age and sex, as well as diet-induced obese and db/db mice, in order to determine the impact of obesity on IL-33 and ST2 gene and protein expression levels in adipose tissue and blood, and their correlation with inflammatory and metabolic parameters. Furthermore, we examined the cellular source and location of IL-33 and ST2 in situ. RESULTS:IL-33 and ST2 expression levels were markedly elevated in omental and subcutaneous adipose tissue of severely obese humans and in diet-induced obese mice, but not in leptin receptor-deficient db/db mice. In addition, soluble ST2, but not IL-33 serum levels, were elevated in obesity. The main source for IL-33 in adipose tissue were endothelial cells, which, in humans, exclusively expressed ST2 on their surface. IL-33 expression strongly correlated with leptin expression in human adipose tissue. CONCLUSIONS:Expression of IL-33 and its receptor ST2 in human adipose tissue is predominantly detectable in endothelial cells and increased by severe obesity indicating an autocrine action. Thus, the adipose tissue microvasculature could participate in obesity-associated inflammation and related complications via IL-33/ST2. 10.1038/ijo.2012.118
    Formyl peptide receptor-2 is upregulated in the blood and placenta of patients with gestational diabetes mellitus. Ye Wenfeng,Chen Linlin,Yang Yanjun,Yao Changfang,Zhu Lihua,Wang Qi,Jiang Jingting The journal of obstetrics and gynaecology research AIM:To investigate the expression of formyl peptide receptor 2 (FPR2) in maternal blood, umbilical blood, and placenta of patients with gestational diabetes mellitus (GDM), and to analyze the changes of other pro-inflammatory cytokines in blood, including interleukin 33 (IL-33), IL-1β, tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP), so as to reveal the pathogenesis of GDM. METHODS:FPR2, IL-33, IL-1β, T TNF-α, and CRP in maternal blood and umbilical cord blood of 50 pregnant women with GDM and 30 normal pregnant women were analyzed by ELISA method to explore the correlation between inflammatory factors and blood glucose. The expression of FPR2 in placental tissues was analyzed by PCR and immunohistochemistry. RESULTS:The expression of FPR2 in maternal blood of gestational diabetes patients was significantly higher than that of normal pregnant women, and other inflammatory factors IL-33 and IL-1β in maternal blood were also significantly increased. The expression of FPR2 in umbilical cord blood of gestational diabetes was higher than that of normal pregnant women, but the difference was not significant. Other inflammatory factors IL-33, IL-1β, and CRP in umbilical cord blood were also significantly increased. The expression of FPR2mRNA and protein in placental tissues of gestational diabetes was significantly higher than that of normal pregnant women. CONCLUSIONS:The level of FPR2, IL-33, and IL-1β in maternal blood was related to the pathogenesis of GDM and these inflammatory factors could be used as special candidate direction of marks for the prevention, clinical treatment and drug design of GDM, laying a new theoretical foundation for the treatment of GDM. 10.1111/jog.14927
    Melatonin Attenuates Contrast-Induced Nephropathy in Diabetic Rats: The Role of Interleukin-33 and Oxidative Stress. Onk Didem,Onk Oruc Alper,Turkmen Kultigin,Erol Huseyin Serkan,Ayazoglu Tulin Akarsu,Keles Osman Nuri,Halici Mesut,Topal Ergun Mediators of inflammation BACKGROUND:Inflammation and oxidative stress (OxS) contribute to the pathogenesis of diabetic kidney disease (DKD) and contrast-induced nephropathy (CIN). Patients with DKD were found to be more prone to CIN. Interleukin-33 (IL-33) is a proinflammatory cytokine, but its role in DKD and CIN is unknown. METHODS:Thirty male Sprague-Dawley rats were enrolled. The first group was comprised of healthy rats (HRs), whereas the other four groups were made up of diabetic rats (DRs), diabetic rats with contrast-induced nephropathy (CIN + DRs), melatonin-treated diabetic rats (MTDRs), and melatonin-treated CIN + DRs (MTCIN + DRs). All groups except the HRs received 50 mg/kg/day streptozotocin (STZ). CIN + DRs were constituted by administrating 1.5 mg/kg of intravenous radiocontrast dye on the 35th day. MTDRs and MTCIN + DRs were given 20 mg/kg/day of intraperitoneal injection of melatonin (MT) from the 28th day for the constitutive seven days. RESULTS:We observed increased IL-33 in the kidney tissue following induction of CIN in DRs. To determine whether MT is effective in preventing CIN, we administered MT in CIN + DRs and demonstrated that kidney tissue levels of OxS markers, inflammatory cytokines, and IL-33 were significantly diminished in MTCIN + DRs compared with other groups without MT treatment (p < 0.05). CONCLUSION:Inhibition of IL-33 with MT provides therapeutic potential in DKD with CIN. 10.1155/2016/9050828
    Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress. Hasnain Sumaira Z,Borg Danielle J,Harcourt Brooke E,Tong Hui,Sheng Yonghua H,Ng Choa Ping,Das Indrajit,Wang Ran,Chen Alice C-H,Loudovaris Thomas,Kay Thomas W,Thomas Helen E,Whitehead Jonathan P,Forbes Josephine M,Prins Johannes B,McGuckin Michael A Nature medicine In type 2 diabetes, hyperglycemia is present when an increased demand for insulin, typically due to insulin resistance, is not met as a result of progressive pancreatic beta cell dysfunction. This defect in beta cell activity is typically characterized by impaired insulin biosynthesis and secretion, usually accompanied by oxidative and endoplasmic reticulum (ER) stress. We demonstrate that multiple inflammatory cytokines elevated in diabetic pancreatic islets induce beta cell oxidative and ER stress, with interleukin-23 (IL-23), IL-24 and IL-33 being the most potent. Conversely, we show that islet-endogenous and exogenous IL-22, by regulating oxidative stress pathways, suppresses oxidative and ER stress caused by cytokines or glucolipotoxicity in mouse and human beta cells. In obese mice, antibody neutralization of IL-23 or IL-24 partially reduced beta cell ER stress and improved glucose tolerance, whereas IL-22 administration modulated oxidative stress regulatory genes in islets, suppressed ER stress and inflammation, promoted secretion of high-quality efficacious insulin and fully restored glucose homeostasis followed by restitution of insulin sensitivity. Thus, therapeutic manipulation of immune regulators of beta cell stress reverses the hyperglycemia central to diabetes pathology. 10.1038/nm.3705
    Stromal cell cadherin-11 regulates adipose tissue inflammation and diabetes. Chang Sook Kyung,Kohlgruber Ayano C,Mizoguchi Fumitaka,Michelet Xavier,Wolf Benjamin J,Wei Kevin,Lee Pui Y,Lynch Lydia,Duquette Danielle,Ceperuelo-Mallafré Victòria,Banks Alexander S,Brenner Michael B The Journal of clinical investigation M2 macrophages, innate lymphoid type 2 cells (ILC2s), eosinophils, Tregs, and invariant NK T cells (iNKT cells) all help to control adipose tissue inflammation, while M1 macrophages, TNF, and other inflammatory cytokines drive inflammation and insulin resistance in obesity. Stromal cells regulate leukocyte responses in lymph nodes, but the role of stromal cells in adipose tissue inflammation is unknown. PDGFRα+ stromal cells are major producers of IL-33 in adipose tissue. Here, we show that mesenchymal cadherin-11 modulates stromal fibroblast function. Cadherin-11-deficient mice displayed increased stromal production of IL-33, with concomitant enhancements in ILC2s and M2 macrophages that helped control adipose tissue inflammation. Higher expression levels of IL-33 in cadherin-11-deficient mice mediated ILC2 activation, resulting in higher IL-13 expression levels and M2 macrophage expansion in adipose tissue. Consistent with reduced adipose tissue inflammation, cadherin-11-deficient mice were protected from obesity-induced glucose intolerance and adipose tissue fibrosis. Importantly, anti-cadherin-11 mAb blockade similarly improved inflammation and glycemic control in obese WT mice. These results suggest that stromal fibroblasts expressing cadherin-11 regulate adipose tissue inflammation and thus highlight cadherin-11 as a potential therapeutic target for the management of obesity. 10.1172/JCI86881
    Effects of combined aerobic and resistance training on the glycolipid metabolism and inflammation levels in type 2 diabetes mellitus. Liu Yuan,Liu Sui-Xin,Cai Ying,Xie Kang-Ling,Zhang Wen-Liang,Zheng Fan Journal of physical therapy science [Purpose] To investigate the effects of combined aerobic and resistance training on glycolipid metabolism and inflammation levels in type 2 diabetes mellitus patients. [Subjects and Methods] Forty-two diabetes patients were randomized to the conventional therapy group (n = 20) or intensive therapy group (n = 22). The control group contained 20 healthy people. The conventional therapy group received routine drug therapy and diet control, while the intensive therapy group additionally underwent combined aerobic and resistance training for 12 weeks. The oral glucose tolerance test and cardiopulmonary exercise testing were performed. Toll-like receptor 4 and NF-κBp65 protein and mRNA expressions were determined by qPCR and western blotting. ELISA was used to determine the expression levels of interleukin-18, interleukin-33, pentraxin-related protein 3, and human cartilage glycoprotein 39. [Results] After exercise training, the intensive therapy group had significantly lower postprandial blood glucose, postprandial insulin, and glycated hemoglobin level and insulin resistance index than the conventional therapy group. The intensive therapy group had significantly lower toll-like receptor 4 and NF-κBp65 protein and mRNA expressions, and serum interleukin-18 levels but significantly higher serum interleukin-33 levels. [Conclusion] Combined aerobic and resistance training can improve glycolipid metabolism and reduce low-grade inflammation in patients with diabetes mellitus patients. 10.1589/jpts.27.2365
    The rs7044343 Polymorphism of the Interleukin 33 Gene Is Associated with Decreased Risk of Developing Premature Coronary Artery Disease and Central Obesity, and Could Be Involved in Regulating the Production of IL-33. Angeles-Martínez Javier,Posadas-Sánchez Rosalinda,Llorente Luis,Alvarez-León Edith,Ramírez-Bello Julian,Villarreal-Molina Teresa,Lima Guadalupe,Cardoso-Saldaña Guillermo,Rodríguez-Pérez José Manuel,Pérez-Hernández Nonanzit,Fragoso José Manuel,Posadas-Romero Carlos,Vargas-Alarcón Gilberto PloS one AIM:The effect of interleukin 33 (IL-33) in the inflammatory process generates significant interest in the potential significance of IL-33 as a biomarker for coronary artery disease (CAD). Here, our objective was to analyze whether IL-33 gene polymorphisms are associated with premature CAD in a case-control association study. METHODS:Four IL-33 polymorphisms (rs7848215, rs16924144, rs16924159 and rs7044343) were genotyped by 5' exonuclease TaqMan assays in 1095 patients with premature CAD and 1118 controls. RESULTS:The rs7044343 T allele was significantly associated with a diminished risk of premature CAD (OR = 0.81, 95% CI: 0.69-0.97, Pdom = 0.020; OR = 0.85, 95% CI: 0.75-0.96, Padd = 0.019) and central obesity (OR = 0.74, 95% CI: 0.58-0.93, Pdom = 0.0007), respectively. When patients were divided into groups with and without type 2 diabetes mellitus (T2DM), the rs7044343 T allele was associated with a reduced risk of premature CAD in patients without (OR = 0.85, 95% CI: 0.73-0.99, Padd = 0.038) and with T2DM (OR = 0.61, 95% CI: 0.38-0.97, Pdom = 0.039; OR = 0.69, 95% CI: 0.49-0.97, Padd = 0.035). In order to establish the functional effect of the rs7044343 polymorphism, the production of IL-33 was determined in monocytes of selected individuals. Monocytes from individuals with rs7044343 CC genotype produced higher levels of IL-33 than monocytes from individuals with other genotypes. CONCLUSION:The results suggest that the IL-33 rs7044343 T allele could be a susceptibility marker for premature CAD and central obesity. The rs7044343 polymorphism could be involved in regulating the production of IL-33. 10.1371/journal.pone.0168828
    CD122 blockade restores immunological tolerance in autoimmune type 1 diabetes via multiple mechanisms. Yuan Xiaomei,Dong Yi,Tsurushita Naoya,Tso J Yun,Fu Wenxian JCI insight Signaling through IL-2/IL-15Rβ (CD122) is essential for the differentiation and function of T cells and NK cells. A mAb against CD122 has been implicated to suppress autoimmune type 1 diabetes (T1D) development in animal models. However, the mechanisms remain poorly understood. We find that in vivo administration of an anti-CD122 mAb (CD122 blockade) restores immune tolerance in nonobese diabetic (NOD) mice via multiple mechanisms. First, CD122 blockade selectively ablates pathogenic NK cells and memory phenotype CD8+ T cells from pancreatic islets. In contrast, islet CD4+Foxp3+ Tregs are only mildly affected. Second, CD122 blockade suppresses IFN-γ production in islet immune cells. Third, CD122 blockade inhibits the conversion of islet Th17 cells into diabetogenic Th1 cells. Furthermore, a combination of anti-CD122 mAb and Treg-trophic cytokines (IL-2 or IL-33) enhances the abundance and function of islet Tregs. In summary, these data provide crucial mechanistic insights into CD122 blockade-mediated immunoregulation and support therapeutic benefits of this combinational treatment in T1D. 10.1172/jci.insight.96600
    IL-33 improves the suppressive potential of regulatory T cells in patients with type 1 diabetes. Ryba-Stanisławowska Monika,Buksa Laura,Brandt Agnieszka,Juhas Ulana,Myśliwiec Małgorzata Diabetes research and clinical practice AIMS:The presented study was aimed to analyze the influence of IL-33 on regulatory T cells (Tregs) suppressive potential in patients with type 1 diabetes. METHODS:We analyzed the ability of IL-33 treated Tregs to inhibit the production of IFN-γ by effector T lymphocytes in an in vitro co-culture. The study group consisted of 22 patients with type 1 diabetes and 12 age and sex-matched healthy individuals. RESULTS:Our findings revealed that in vitro IL-33 treatment of Tregs derived from patients with type 1 diabetes resulted in quantitative as well as qualitative changes in this cell population, confirming immunoregulatory features of IL-33. CONCLUSION:IL-33 could be considered as a potential therapeutic tool in adoptive therapies of type 1 diabetes. 10.1016/j.diabres.2017.04.011
    Reduction in IL-33 expression exaggerates ischaemia/reperfusion-induced myocardial injury in mice with diabetes mellitus. Rui Tao,Zhang Jinchao,Xu Xuemei,Yao Yongwei,Kao Raymond,Martin Claudio M Cardiovascular research AIMS:The underlying mechanism(s) of vulnerability of the diabetic myocardium to ischaemia/reperfusion (I/R)-induced injury is not fully understood. Interleukin-33 (IL-33) has been reported showing the beneficial effect to the myocardium on I/R injury. The aims of this study were to test whether diabetes mellitus (DM) affects myocardial levels of IL-33 and to examine whether reduction in IL-33 is responsible for exaggerated I/R injury in the diabetic myocardium. METHODS AND RESULTS:DM hearts were challenged with I/R in vivo, whereas while isolated cardiomyocytes in vitro were conditioned with high glucose (HG) followed by an anoxia/reoxygenation (A/R) challenge. Myocardial levels of IL-33 were decreased in mice with DM which was associated with increased protein kinase C βII (PKCβII) activation. Exogenous IL-33 prevented the DM-induced PKCβII activation and attenuated I/R injuries (myocardial infarction size and apoptosis). HG-conditioned myocytes incurred exaggerated apoptosis when compared with naïve myocytes after A/R which was attenuated by IL-33. HG activated PKCβII in cardiomyocytes, which was further enhanced by A/R. IL-33 prevented the PKCβII activation in myocytes with HG or HG and A/R. Inhibition of PKCβII prevented the beneficial effect of IL-33. Finally, IL-33 up-regulated diacylglycerol kinase zeta (DGK-zeta) in cardiomyocytes and reversed the down-regulation of myocardial DGK-zeta in mice with DM. CONCLUSION:Our results indicate that decreased levels of IL-33 are responsible for the increased sensitivity of the myocardium to I/R in DM. Reduction in IL-33 results in a chronic activation of PKCβII. I/R further enhances PKCβII activation in the diabetic myocardium which results in exaggeration of myocardial injury. 10.1093/cvr/cvs015
    Increased serum levels of novel T cell cytokines IL-33, IL-9 and IL-17 in subjects with type-1 diabetes. Shruthi Sugumar,Mohan Viswanathan,Amutha Anandakumar,Aravindhan Vivekanandhan Cytokine The role of adaptive immune cytokines in the pathogenesis of type-1 Diabetes Mellitus (T1DM) is well known. Even though reports on the serum levels of both Th-1 and Th-2 cytokines are available, those on newly described T cell cytokines such as IL-17, IL-33 and IL-9 in T1DM are scarce. We therefore measured the serum levels of both T cell polarizing (IL-33 and IL-12) and T cell effector (IFN-γ, IL-4, IL-10, IL-17 and IL-9) cytokines in T1DM subjects with and without microvascular (retinopathy and nephropathy) complications (MVC). All the tested cytokines were significantly elevated in T1DM subjects except for IFN-γ (which failed to attain statistical significance) with no significant difference between those with and without MVC. From the serum cytokine analysis, no apparent Th polarization could be determined for the T1DM subjects. 10.1016/j.cyto.2016.07.007
    IL33/ST2 Axis in Diabetic Kidney Disease: A Literature Review. Tonacci Alessandro,Quattrocchi Paolina,Gangemi Sebastiano Medicina (Kaunas, Lithuania) Interleukin-33 (IL-33) is a cytokine belonging to the IL-1 family, playing a role in inflammatory, infectious and autoimmune diseases and expressed in the cellular nucleus in several tissues. High levels of IL-33 are expressed in epithelial barrier tissues and endothelial barriers. ST2 is a receptor for IL-33, expressed selectively on a subset of Th2 cells, mediating some of their functions. The IL-33/ST2 axis plays an important role in several acute and chronic inflammatory diseases, including asthma and rheumatoid arthritis. Different disorders are related to the activity of IL-33, ST2, or their axis, including cardiovascular disease or renal disturbances. Therefore, in the present work, a literature review was conducted, covering the period from 1 January 2000 to 30 November 2018, in PubMed, ScienceDirect, and Google Scholar database, to assess the involvement of the IL-33/ST2 axis in diabetic kidney disease. 6 articles directly dealing with the argument were identified, highlighting a clear link between IL-33/ST2 axis and diabetic kidney disease or related nephropathy. Overall, the involvement of ST2 seems to be more predictive than IL-33, especially in investigating the deterioration of kidney function; however, both compounds are pivotal in the field of renal diseases. Future studies are required to confirm the scientific evidences on larger and more heterogeneous cohorts. 10.3390/medicina55020050
    IL-33 Prevents MLD-STZ Induction of Diabetes and Attenuate Insulitis in Prediabetic NOD Mice. Pavlovic Sladjana,Petrovic Ivica,Jovicic Nemanja,Ljujic Biljana,Miletic Kovacevic Marina,Arsenijevic Nebojsa,Lukic Miodrag L Frontiers in immunology Type 1 diabetes is an autoimmune disease caused by the immune-mediated destruction of pancreatic β-cells. Prevention of type 1 diabetes requires early intervention in the autoimmune process against beta-cells of the pancreatic islets of Langerhans, which is believed to result from disordered immunoregulation. CD4Foxp3 regulatory T cells (Tregs) participate as one of the most important cell types in limiting the autoimmune process. The aim of this study was to investigate the effect of exogenous IL-33 in multiple low dose streptozotocin (MLD-STZ) induced diabetes and to delineate its role in the induction of protective Tregs in an autoimmune attack. C57BL/6 mice were treated i. p. with five doses of 40 mg/kg STZ and 0.4 μg rIL-33 four times, starting from day 0, 6, or 12 every second day from the day of disease induction. 16 weeks old NOD mice were treated with 6 injections of 0.4 μg/mouse IL-33 (every second day). Glycemia and glycosuria were measured and histological parameters in pancreatic islets were evaluated at the end of experiments. Cellular make up of the pancreatic lymph nodes and islets were evaluated by flow cytometry. IL-33 given simultaneously with the application of STZ completely prevented the development of hyperglycemia, glycosuria and profoundly attenuated mononuclear cell infiltration. IL-33 treatment was accompanied by higher number of IL-13 and IL-5 producing CD4 T cells and increased presence of ST2Foxp3 regulatory T cells in pancreatic lymph nodes and islets. Elimination of Tregs abrogated protective effect of IL-33. We provide evidence that exogenous IL-33 completely prevents the development of T cell mediated inflammation in pancreatic islets and consecutive development of diabetes in C57BL/6 mice by facilitating the induction Treg cells. To extend this finding for possible relevance in spontaneous diabetes, we showed that IL-33 attenuate insulitis in prediabetic NOD mice. 10.3389/fimmu.2018.02646
    Renoprotective effect of calycosin in high fat diet-fed/STZ injected rats: Effect on IL-33/ST2 signaling, oxidative stress and fibrosis suppression. Elsherbiny Nehal M,Said Eman,Atef Hoda,Zaitone Sawsan A Chemico-biological interactions Type 2 diabetes mellitus (T2DM) is a disease with a drastically growing worldwide prevalence. It is usually associated with numerous complications of which; diabetic nephropathy (DN); is a main complication of microvasculature and more seriously, a common cause of end-stage renal disease (ESRD). Unfortunately, both the lack of a definitive remedy alongside the economic and the social burden on DN patients enforces considerable impetus for developing alternative therapies. IL-33 is a newly discovered member of the IL-1 cytokine family. IL33/ST2 signaling plays a crucial role in acute and chronic kidney diseases. Calycosin is an isoflavone with reported IL33 signaling inhibitory activity. The present study aimed to investigate if calycosin possess renal protective effect in high-fat diet/STZ-induced T2DM model and to clarify the potential underlying mechanisms. HFD-STZ control rats showed functional and structural renal damage confirmed by increased serum creatinine, blood urea nitrogen and albuminuria associated with marked renal glomerulosclerosis and interstitial fibrosis. Initiation of inflammation, oxidative stress, and fibrosis was evident as depicted by elevated renal levels of IL33/ST2 mRNA as well as increased renal NF-κBp65, TNF-α, IL-1β, MDA, and TGF-β contents with suppressed Nrf2 and TAC. Calycosin treatment markedly improved the aforementioned makers of renal injury and dysfunction, modulated IL33/ST2 signaling, inflammatory cytokines, oxidative stress and fibrotic processes. This was accompanied by improvement of T2DM-induced renal ultramicroscopic and histopathological alterations. 10.1016/j.cbi.2019.108897
    Early high plasma ST2, the decoy IL-33 receptor, in children undergoing hematopoietic cell transplantation is associated with the development of post-transplant diabetes mellitus. Rowan Courtney M,Teagarden Alicia M,Cater Daniel T,Moser Elizabeth A S,Baykoyannis Giorgos,Paczesny Sophie Haematologica 10.3324/haematol.2019.222992
    DR3 stimulation of adipose resident ILC2s ameliorates type 2 diabetes mellitus. Shafiei-Jahani Pedram,Hurrell Benjamin P,Galle-Treger Lauriane,Helou Doumet Georges,Howard Emily,Painter Jacob,Lo Richard,Lewis Gavin,Soroosh Pejman,Akbari Omid Nature communications Disturbances in glucose homeostasis and low-grade chronic inflammation culminate into metabolic syndrome that increase the risk for the development of type 2 diabetes mellitus (T2DM). The recently discovered group 2 innate lymphoid cells (ILC2s) are capable of secreting copious amounts of type 2 cytokines to modulate metabolic homeostasis in adipose tissue. In this study, we have established that expression of Death Receptor 3 (DR3), a member of the TNF superfamily, on visceral adipose tissue (VAT)-derived murine and peripheral blood human ILC2s is inducible by IL-33. We demonstrate that DR3 engages the canonical and/or non-canonical NF-κB pathways, and thus stimulates naïve and co-stimulates IL-33-activated ILC2s. Importantly, DR3 engagement on ILC2s significantly ameliorates glucose tolerance, protects against insulin-resistance onset and remarkably reverses already established insulin-resistance. Taken together, these results convey the potent role of DR3 as an ILC2 regulator and introduce DR3 agonistic treatment as a novel therapeutic avenue for treating T2DM. 10.1038/s41467-020-18601-7
    Interleukin-33 rescues perivascular adipose tissue anticontractile function in obesity. Saxton Sophie N,Whitley Alice S,Potter Ryan J,Withers Sarah B,Grencis Richard,Heagerty Anthony M American journal of physiology. Heart and circulatory physiology Perivascular adipose tissue (PVAT) depots are metabolically active and play a major vasodilator role in healthy lean individuals. In obesity, they become inflamed and eosinophil-depleted and the anticontractile function is lost with the development of diabetes and hypertension. Moreover, eosinophil-deficient ΔdblGATA-1 mice lack PVAT anticontractile function and exhibit hypertension. Here, we have investigated the effects of inducing eosinophilia on PVAT function in health and obesity. Control, obese, and ΔdblGATA-1 mice were administered intraperitoneal injections of interleukin-33 (IL-33) for 5 days. Conscious restrained blood pressure was measured, and blood was collected for glucose and plasma measurements. Wire myography was used to assess the contractility of mesenteric resistance arteries. IL-33 injections induced a hypereosinophilic phenotype. Obese animals had significant elevations in blood pressure, blood glucose, and plasma insulin, which were normalized with IL-33. Blood glucose and insulin levels were also lowered in lean treated mice. In arteries from control mice, PVAT exerted an anticontractile effect on the vessels, which was enhanced with IL-33 treatment. In obese mice, loss of PVAT anticontractile function was rescued by IL-33. Exogenous application of IL-33 to isolated arteries induced a rapidly decaying endothelium-dependent vasodilation. The therapeutic effects were not seen in IL-33-treated ΔdblGATA-1 mice, thereby confirming that the eosinophil is crucial. In conclusion, IL-33 treatment restored PVAT anticontractile function in obesity and reversed development of hypertension, hyperglycemia, and hyperinsulinemia. These data suggest that targeting eosinophil numbers in PVAT offers a novel approach to the treatment of hypertension and type 2 diabetes in obesity. In this study, we have shown that administering IL-33 to obese mice will restore PVAT anticontractile function, and this is accompanied by normalized blood pressure, blood glucose, and plasma insulin. Moreover, the PVAT effect is enhanced in control mice given IL-33. IL-33 induced a hypereosinophilic phenotype in our mice, and the effects of IL-33 on PVAT function, blood pressure, and blood glucose are absent in eosinophil-deficient mice, suggesting that the effects of IL-33 are mediated via eosinophils. 10.1152/ajpheart.00491.2020
    Interleukin-33 prevents the development of autoimmune diabetes in NOD mice. Lu Jingli,Liang Yan,Zhao Junjie,Meng Haiyang,Zhang Xiaojian International immunopharmacology IL-33/ST2 signal is important for the generation of forkhead box P3 (Foxp3) regulatory (Treg) cells, which contribute to immune homeostasis in the context of diseases. The aim of this study was to determine whether targeting IL-33/ST2 signal could establish immunological tolerance and prevent type 1 diabetes (T1D) in nonobese diabetic (NOD) mice. Female NOD mice treated with IL-33 for 4 weeks decreased the incidence and delayed the onset of autoimmune diabetes, whereas IL-33 did not revert blood glucose concentration and disease development in mice with new-onset diabetes. IL-33 reduced immune cell infiltration, increased the number of insulin-positive islet cells, as well as increased antiapoptosis molecule Bcl2 and reduced proapoptosis molecules Caspase3 at mRNA levels in the pancreas. IL-33 increased the expression of phosphorylated-Akt and phosphorylated-PI3K in the pancreas. Systemic administration of IL-33 increased the number of CD4CD25Foxp3Treg cells and induced expression of Treg cell-associated molecules ST2 and GATA3 in splenic lymphocytes, and increased Foxp3, Ctla4, and Gata3 at the -mRNA level in pancreatic lymph nodes of NOD mice. IL-33 signaling stimulated activation of phosphorylation of p44/42 (Erk) and p38 MAPK, as well as CD39 in the spleen. Our results showed that IL-33 prevents disease development in prediabetic NOD mice, and highlight IL-33/ST2 as a potential therapeutic target to prevent T1D. 10.1016/j.intimp.2019.02.018
    The effect of diabetes on ovaries in a rat model: the role of interleukin-33 and apoptosis. Nayki Cenk,Nayki Umit,Kulhan Mehmet,Ozkaraca Mustafa,Altun Serdar,Cankaya Murat,Onk Oruc Alper,Ulug Pasa Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology Interleukin-33 (IL-33) is a novel cytokine involved in diabetes mellitus (DM) but its role in diabetic ovarian injury is unknown. As IL-33 is modulated by apoptosis, we aimed at investigating the effect of diabetes on ovaries in terms of evaluating apoptosis and IL-33 in a rat model. In this prospective experimental study, 16 female, nonpregnant Sprague-Dawley albino rats (12 weeks, 220-240 g) were randomly divided into two groups. Group 1 included eight healthy nondiabetic rats as controls and group 2 included eight rats in which diabetes was induced by intraperitoneal (i.p) injection of streptozotocin (STZ). After overt DM occurred (blood glucose >400 mgr/dl), all animals were euthanized and blood samples were collected by cardiac puncture for biochemical analysis. Bilateral oophorectomy was performed for histopathological examination. Serum levels of IL-33 and ovarian IL-33 and caspase-3 immunoexpressions were assessed. Immunoexpressions of caspase-3 and IL-33 were significantly higher in ovarian stromal cells of the diabetic rats compared to the controls. Also, in diabetic group, serum IL33 levels were significantly higher than the control group. In conclusion, increased IL-33 was observed both in serum and ovaries of STZ-induced diabetic rats as well as increased apoptosis in these diabetic rats. IL-33 may contribute to the apoptosis in diabetic ovarian injury. 10.1080/09513590.2017.1313971