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介素-19 (IL-19)，一种Th2抗炎白介素，可以减轻动脉粥样硬化，并确定这种抑制的潜在机制。IL-19是一种新发现的Th2 （T调节性）抗炎白介素，在我们的研究之前，它一直被认为是炎症细胞特异性的。我们仍然是唯一一个研究这种白细胞介素在血管生物学中的作用的实验室，特别是在EC和VSMC病理生理方面，并证明了这些作用的分子机制。我们之前报道过；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中诱导；2-在VSMC中添加IL-19可减少其迁移、增殖以及增殖性和炎性蛋白的丰度；3- IL-19不抑制NF-kB，但确实以hr依赖的方式降低炎症和增殖mRNA转录物的稳定性；4- IL-19诱导血管和细胞保护蛋白血红氧合酶-1 （HO-1）的表达，并以HO-1依赖的方式减少血管活性氧（ROS）诱导的细胞凋亡。在这项应用中，我们提供的初步数据显示，在喂食致动脉粥样硬化饮食的LDLR-/-小鼠中添加重组IL-19可以显著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。基于已发表的和初步的数据，我们假设这些保护作用有多种多样的机制，并且设计了特异性目标来测试这些机制。在Aim 1中，我们将确定IL-19的缺失是否会加剧动脉粥样硬化，而过表达是否会减轻动脉粥样硬化。目的2将验证IL-19保护的一种机制主要是通过对Th2的过继性免疫系统极化来促进的假设。目的3将验证IL-19动脉粥样硬化保护是通过白细胞-内皮细胞相互作用减少和/或IL-19诱导HO-1表达介导的。目的4将确定IL- 19如何降低炎症基因丰度的分子机制。这一应用可能会改变范式，因为它将涉及Th2白细胞介素作为炎症血管细胞表达的内源性细胞因子，具有多种自分泌和旁分泌抑制作用。它将在这些细胞中发现新的分子机制和抗炎途径的靶点。

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.