Suppression of VSMC Activation and Mechanisms of Vascular Protection by IL-19

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DESCRIPTION (provided by applicant): The development of multiple vascular diseases ranging from atherosclerosis to transplant vasculopathy are inflammatory in nature. Although much is known about the deleterious effects of pro-inflammatory cytokines on vascular smooth muscle cells (VSMC) pathophysiology, we know very little about the direct protective effects of anti-inflammatory cytokines on VSMC. Our overall hypothesis is that IL -19 plays a protective role in the vascular response to injury by direct inhibitory effects on VSMC activation. IL-19 is a recently described member of the IL -10 family of anti-inflammatory cytokines. IL-19 expression is ascribed to be restricted to hematopoetic and inflammatory cells, where it has an anti-inflammatory effect. Nothing has been reported on the mechanism(s) of IL-19 effects, either in immune or vascular cells. We have found that; IL-19 is not expressed in quiescent VSMC or normal arteries, but is induced in VSMC by inflammatory cytokines and in arteries by injury; IL -19 is anti-proliferative for cultured, human coronary artery VSMC, induces activation of STAT-3; inhibits activation of signal transduction MAPK and expression of proliferative and inflammatory genes. IL -19 induces expression of the suppressor of cytokine signaling 5 (SOCS5), but inhibits expression and translocation of HuR, a stability factor which regulates decay of inflammatory and proliferative gene mRNA. IL-19 adenoviral gene transfer significantly reduces neointimal formation and VSMC proliferation in balloon angioplasty-injured rat carotid arteries. The overall goals of this application are designed to characterize the mechanism of IL -19 suppressive effects on VSMC and development of progression of intimal hyperplasia in response to vascular injury. We will test the hypothesis that STAT3 activation, SOCS5 expression, and HuR down-regulation are critical events in IL -19 mediated VSMC protection. We will test the hypothesis that IL-19 has protective effects on VSMC by decreasing expression of proliferative and inflammatory genes, and will define the mechanism(s) of these effects. We will test the hypothesis that IL -19 anti-restenotic effects in vivo are due at least in part by attenuation of inflammatory and proliferative gene expression, mediated by expression of SOCS5 and down regulation of HuR. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the number one cause of mortality in the United States and places an enormous medical and economic burden on our society. This application will address the novel concept of direct beneficial effects of anti- inflammatory cytokines on vascular pathophysiology.