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

描述（由申请人提供）：从动脉粥样硬化到移植血管病变的多种血管疾病的发展本质上是炎症性的。尽管促炎细胞因子对血管平滑肌细胞（VSMC）的病理生理学的有害作用已知之甚多，但我们对抗炎细胞因子对VSMC的直接保护作用知之甚少。我们的总体假设是IL-19通过直接抑制VSMC活化在血管对损伤的反应中起保护作用。IL-19是最近描述的抗炎细胞因子IL-10家族的成员。IL-19的表达被认为局限于造血和炎症细胞，在那里它具有抗炎作用。关于IL-19在免疫细胞或血管细胞中的作用机制尚未报道。我们发现，IL-19在静止的VSMC或正常动脉中不表达，但在VSMC中由炎性细胞因子诱导，在动脉中由损伤诱导; IL-19对培养的人冠状动脉VSMC具有抗增殖作用，诱导STAT-3的活化;抑制信号转导MAPK的活化以及增殖和炎性基因的表达。IL-19诱导细胞因子信号传导抑制因子5（SOCS 5）的表达，但抑制HuR的表达和易位，HuR是调节炎症和增殖基因mRNA衰变的稳定因子。IL-19腺病毒基因转移显著减少球囊血管成形术损伤大鼠颈动脉的新生内膜形成和VSMC增殖。本申请的总体目标旨在表征IL-19对VSMC的抑制作用机制以及响应血管损伤的内膜增生进展的发展。我们将检验STAT 3激活、SOCS 5表达和HuR下调是IL-19介导的VSMC保护中的关键事件的假设。我们将检验IL-19通过降低增殖和炎症基因的表达对VSMC具有保护作用的假设，并将确定这些作用的机制。我们将检验IL-19体内抗再狭窄作用至少部分是由于SOCS 5表达和HuR下调介导的炎性和增殖性基因表达减弱所致的假设。公共卫生相关性：心血管疾病是美国的头号死亡原因，给我们的社会带来了巨大的医疗和经济负担。本申请将阐述抗炎细胞因子对血管病理生理学的直接有益作用的新概念。

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.