Interleukin-33/ST2 in cardiovascular pathophysiology

Interleukin (IL)-33 is the most recently described member of the IL-1 family of cytokines and a ligand for ST2 receptor. IL-33 exists both as an intracellular effector in its full length propeptide form and as an extracellular ligand in its cleaved mature form. Although IL-33 is structurally related to other members of IL-1 family of cytokines, such as IL-1 and IL-18, it shows different expression and functional patterns. In addition to studies describing of a role of IL-33/ST2 in the pathogenesis of "classical" inflammatory disorders, this system has recently also been shown to participate in cardiovascular pathophysiology. Cardiac ST2 is up regulated after myocardial infarction (MI) in mice, and soluble ST2 is recognized as a biomarker in patients with MI and heart failure (HF). It was also shown that the absence of ST2 decreased cardiac function and survival after ventricular pressure overload in mice. Treatment of atherosclerosis-prone Apolipoprotein E (ApoE) knockout (ApoE-/- ) mice with IL-33 reduced atherosclerotic plaque development. The responsible mechanisms for the beneficial effects of IL-33/ST2 signalling in the cardiovascular system, however, remain uncertain. Exploration of the interplay between the components of immune-inflammatory milieu during ischemia and atherosclerosis and IL-33 expression seems also to be warranted. Here we plan to study expression, regulation and functions of the IL-33/ST2 system in human cardiac cells (fibroblasts and myocytes) and vascular cells (coronary artery and aorta smooth muscle and endothelial cells) in vitro, in human failing heart tissue ex vivo, and in murine models of MI and atherosclerosis in vivo. In cells in vitro we plan to study the regulation of IL-33 and ST2 by hypoxia, pro-inflammatory cytokines IL-1ß, IL-18, tumor necrosis factor-a and interferon-, members of the glycoprotein 130 cytokine family, and T helper type 2 lymphocytes-associated cytokines IL-4 and IL-10. To examine the potential functional role of IL-33/ST2 signalling during myocardial ischemia and in atherosclerosis, we plan to use ST2 knockout (ST2-/- ) mice and to generate ApoE -/- /ST2 -/- double knockout mice, respectively. In IL-33-treated cells, in ST2-/- mice following MI, and in ApoE -/- /ST2 -/- mice we plan to measure the components of the matrix metalloproteinases (MMP)issue inhibitors of MMP (TIMP) and plasminogen/plasmin systems, transforming growth factor-ß, chemokines monocyte chemoattractant protein-1 and IL-8, and the macrophages/granulocytes maturation factors macrophage colony stimulating factor (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) RNA expression and protein production. Heart and vessel remodeling is an important feature that determines survival of patients with atherosclerosis, MI and HF. To delineate a potential functional role of IL-33 in these pathologies could establish the IL-33/ST2 system as a candidate for the development of new therapeutic strategies to combat cardiovascular disease.