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

描述(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。虽然促炎细胞因子对血管平滑肌细胞(VSMC)的病理生理有害作用已知很多，但对抗炎细胞因子对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的激活，在血管损伤反应中发挥保护作用。IL-19是新近发现的IL-10抗炎细胞因子家族成员。IL-19的表达被认为仅限于造血细胞和炎性细胞，在这些细胞中它具有抗炎作用。目前还没有关于IL-19在免疫细胞和血管细胞中的作用机制的报道(S)。我们发现：IL-19在静止的VSMC和正常动脉不表达，但在炎症细胞因子诱导的VSMC和损伤的动脉中表达；IL-19对培养的人冠状动脉VSMC具有抗增殖作用，诱导STAT-3的激活；抑制信号转导MAPK的激活和增殖和炎症基因的表达。IL-19诱导细胞因子信号转导抑制因子5(SOCS5)的表达，但抑制Hur的表达和转位，Hur是一种稳定因子，调节炎症和增殖基因mRNA的衰退。IL-19腺病毒基因转移显著减少球囊血管成形术损伤的大鼠颈动脉新生内膜形成和VSMC增殖。这项应用的总体目标是研究IL-19抑制血管SMC的作用机制以及血管损伤后内膜增生的进展情况。我们将检验这一假设，即STAT3激活、SOCS5表达和HUR下调是IL-19介导的VSMC保护的关键事件。我们将验证IL-19通过减少增殖和炎症基因的表达而对血管平滑肌细胞具有保护作用的假说，并将确定这些作用的机制(S)。我们将验证这一假说，即IL-19在体内的抗再狭窄作用至少部分是由于SOCS5的表达和Hur的下调介导的炎症和增殖基因表达的减弱。公共卫生相关性：心血管疾病是美国头号死亡原因，给我们的社会带来了巨大的医疗和经济负担。这项应用将解决抗炎细胞因子对血管病理生理学的直接有益作用这一新概念。

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.