Obesity, characterized by an increase in adipose tissue mass, is a major risk factor for the development of a wide array of metabolic disorders including insulin resistance, glucose intolerance, and type 2 diabetes mellitus. Obesity can be associated with increased concentrations of low density lipoprotein cholesterol (LDL-C) and triglycerides (TGL), which play an important role in the development of atherosclerosis and coronary artery disease (CAD)[3–6]. Obesity is associated with a state of chronic low-grade inflammation, which plays a role in the development of both atherosclerosis and diabetes. In this regard, T cells and macrophages accumulate in the adipose tissue and secrete various proinflammatory cytokines and chemokines including tumour necrosis factor-alpha (TNF-α), interleukin-6, interleukin-8, C-reactive protein, plasminogen activator inhibitor-1, resistin, angiotensinogen and monocyte chemoattractant protein-1[9, 10]. Similarly, the accumulation of macrophage-derived foam cells[11, 12] and T helper type 1 (Th1) cells within atherosclerotic plaques, and the resultant chronic inflammation of the arterial wall, plays a key role in plaque progression.
Interleukin-33 (IL-33), a newly identified cytokine of the interleukin-1 (IL-1) family, is broadly expressed in various tissue types[15, 16] and is mainly present in stromal cells such as endothelial, epithelial and myocardial cells[16, 17], as well as pre-adipocytes and adipocytes. The receptor for IL-33 is ST2, which is a member of the IL-1 receptor family. IL-33 has been shown to be proinflammatory in certain conditions such as allergy and autoimmunity and to be protective in others such as obesity, atherosclerosis and cardiac fibrosis.
The metabolic effects of IL-33 in obesity have mostly been investigated in murine models[16, 18, 21]. In this regard, studies have shown that IL-33 exerts protective metabolic effects[16, 18] through several mechanisms: (1) IL-33 decreases the expression of resistin (a mediator that is responsible for the development of insulin resistance and type 2 diabetes mellitus), (2) leads to the accumulation of protective Th2 cells and their cytokines, and (3) leads to the polarization of resident macrophages towards a protective alternatively activated phenotype (CD206+ M2)[16, 18]. These findings were further supported by in vitro studies showing that the treatment of murine adipocytes with IL-33 induces the production of protective Th2 cytokines (mainly IL-5 and IL-13), reduces lipid storage and decreases the expression of genes associated with lipid metabolism and adipogenesis[16, 18]. Moreover, IL-33 administration to diabetic obese (ob/ob) mice results in reduced adiposity and fasting glucose, as well as improved glucose and insulin tolerance[16, 18]; whereas feeding ST2-/- mice a high fat diet leads to increased body weight, fat mass, impaired insulin secretion and glucose regulation[16, 18, 21].
Similarly, studies in murine (ApoE-/-) models have reported a protective role for IL-33, when administered systemically, against the development of atherosclerosis and cardiovascular disease. The protective properties of IL-33 are exerted by the induction of a potent instigation from a pro-atherogenic Th1 to a protective Th2 phenotype, and by the expansion of suppressive CD4+ FOXP3+ ST2L+ regulatory T cells. In this regard, IL-33 increases Th2 (IL-4, IL-5, and IL-13) but decreases Th1 (IFN-γ) cytokine production, and increases total serum immunoglobulin-A (IgA), IgE and IgG1 but decreases IgG2a, which collectively indicate a switch from a Th1 to a Th2 phenotype. Moreover, IL-33 blocks the differentiation of macrophage-derived foam cells, which are responsible for the formation of atherosclerotic plaques. Mice treated intraperitoneally with IL-33 exhibit smaller atherosclerotic lesions in the aortic sinus and have fewer macrophages and T-cells; whereas those treated with sST2 (a decoy receptor that neutralizes IL-33) develop larger atherosclerotic plaques when compared to controls. Anti-oxidized LDL-C antibodies are thought to be protective against the development of atherosclerosis by enhancing the clearance of oxLDL-C from the circulation. Indeed, a recent study has proposed a role for IL-33 in the induction of anti-ox-LDL-C antibodies. Furthermore, mice treated with IL-33 produce elevated levels of protective anti-ox-LDL-C antibodies via an effect on B1 cells, which produce high levels of IgM autoantibodies.
Collectively, the aforementioned studies suggest a protective role for IL-33 against the development of obesity-associated inflammation and atherosclerosis. However, little is known about the role of IL-33 in human obesity and its associated anomalies such as atherosclerosis. In addition, there are no correlation studies between IL-33 and important clinical parameters such as body mass index (BMI), serum lipids, and HbA1c. Therefore, we sought to investigate whether obesity is associated with lower circulating levels of IL-33, and whether IL-33 is associated with clinical parameters. Herein, we show that IL-33 is reduced in non-lean subjects, and that IL-33 is negatively correlated with the BMI and body weight in lean and overweight, but not obese (non-diabetic and diabetic), subjects. In addition, we show that 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.