Interleukin-19 Inhibits Atherosclerosis by Diverse Mechanisms

描述（由申请人提供）：本申请的总体目标是证明白细胞介素-19（IL-19）（一种Th 2抗炎白细胞介素）可以减轻动脉粥样硬化，并鉴定这种抑制的潜在机制。IL-19是一种新发现的Th 2（T调节）抗炎白细胞介素，在我们的工作之前，它一直被认为是炎症细胞特异性的。我们仍然是唯一的实验室，调查这种白细胞介素在血管生物学中的作用，特别是在EC和VSMC病理生理学方面，并证明这些作用的分子机制。我们以前报道过; 1- IL-19在正常动脉中检测不到，但在人动脉粥样硬化病变的EC和VSMC中被诱导; 2-向VSMC中添加IL-19降低它们的迁移、增殖以及增殖和炎性蛋白的丰度; 3- IL-19不抑制NF-κ B，但以HuR依赖的方式降低炎性和增殖mRNA转录物的稳定性; 4- IL-19诱导血管和细胞保护蛋白血红素加氧酶-1（HO-1）的表达，并以HO-1依赖性方式减少由血管活性氧（ROS）诱导的细胞凋亡。在本申请中，我们提供的初步数据显示，向喂食致动脉粥样硬化饮食的LDLR-/-小鼠中添加重组IL-19显著且显著地减少动脉粥样硬化斑块，并且IL-19-/-小鼠对结扎损伤的反应加剧。根据已发表的和初步的数据，我们假设这些保护作用有多种多效性机制，并设计了特定目的来测试这些机制中的每一种。在目标1中，我们将确定IL-19的缺乏是否会加重动脉粥样硬化，以及过度表达是否会减轻动脉粥样硬化。目的2将检验IL-19保护的一种机制主要通过过继免疫系统极化至Th 2来促进的假设。目的3将检验IL-19动脉粥样硬化保护作用是通过减少白细胞-内皮细胞相互作用和/或IL-19诱导HO-1表达介导的假设。目的4将确定IL- 19如何减少炎症基因丰度的分子机制。这种应用是潜在的范式改变，因为它将涉及Th 2白细胞介素作为一种内源性细胞因子，由发炎的血管细胞表达，具有多种自分泌和旁分泌抑制作用。它将确定这些细胞中抗炎途径的新分子机制和靶点。

DESCRIPTION (provided by applicant): The overall goals of this application are to demonstrate that Interleukin-19 (IL-19), a Th2 anti- inflammatory interleukin, can attenuate atherosclerosis, and identify the potential mechanisms of this inhibition. IL-19 is a newly described Th2, (T regulatory) anti-inflammatory interleukin which until our work, had been ascribed to be inflammatory cell-specific. We remain the only laboratory to investigate a role for this interleukin in vascular biology, particularly with respect to EC and VSMC pathophysiology, and to demonstrate molecular mechanisms for these effects. We previously reported that; 1- IL-19 is not detectible in normal artery, but is induced in EC and VSMC in human atherosclerotic lesions; 2- addition of IL-19 to VSMC reduces their migration, proliferation, and abundance of proliferative and inflammatory proteins; 3- IL-19 does NOT inhibit NF-kB, but does reduce the stability of inflammatory and proliferative mRNA transcripts in an HuR-dependent manner; 4- IL-19 induces expression of the vascular and cyto-protective protein Hemeoxygenase-1 (HO-1), and reduces apoptosis induced by vascular reactive oxygen species (ROS) in an HO-1 dependent manner. In this application we present preliminary data showing that addition of recombinant IL-19 to LDLR-/- mice fed an atherogenic diet significantly and dramatically decreases atherosclerotic plaque, and IL-19-/- mice have an exacerbated response to ligation injury. Based on published and preliminary data, we hypothesize that there are multiple, pleiotropic mechanisms for these protective effects, and Specific Aims are designed to test each of these mechanisms. In Aim 1, we will determine if absence of IL-19 exacerbates, and if over expression attenuates atherosclerosis. Aim 2 will test the hypothesis that one mechanism of IL-19 protection is primarily facilitated by adoptive immune system polarization to Th2. Aim 3 will test the hypothesis that IL-19 atheroprotection is mediated by reduction in leukocyte-endothelial cell interaction, and/or IL-19 induction of HO-1 expression. Aim 4 will determine the molecular mechanisms of how IL- 19 decreases inflammatory gene abundance. This application is potentially paradigm-changing as it will implicate a Th2 interleukin as an endogenous cytokine expressed by inflamed vascular cells with multiple autocrine and paracrine dampening effects. It will identify novel molecular mechanisms and targets of anti-inflammatory pathways in these cells.