Interleukin-19 Inhibits Atherosclerosis by Diverse Mechanisms

Interleukin-19 通过多种机制抑制动脉粥样硬化

• 批准号: 8878340
• 负责人: MICHAEL V AUTIERI
• 金额: $ 41.77万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-23 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8878340
• 关键词: Accounting; Adhesions; Adoptive Transfer; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Apoptosis; Arterial Fatty Streak; Arteries; Atherogenic Diet; Atherosclerosis; Attenuated; Biology; Blood Vessels; Cell Adhesion Molecules; Cell Communication; Cells; Characteristics; Cultured Cells; Data; Disease; Disease model; Endothelial Cells; Event; Functional disorder; Genes; Goals; Health; Human; Immune; Immune system; In Vitro; Inflammation; Inflammatory; Injury; Interleukins; Laboratories; Leukocytes; Ligation; Mediating; Messenger RNA; Modality; Modeling; Molecular; Mus; NF-kappa B; Pathway interactions; Phenotype; Proteins; Publishing; Reactive Oxygen Species; Recombinant Interleukins; Reporting; Role; Serum; Severities; Smooth Muscle Myocytes; Source; Stimulus; Testing; Transcript; United States; Vascular Diseases; Work; adaptive immunity; atherogenesis; autocrine; base; cytokine; design; feeding; heme oxygenase-1; in vivo; injured; interleukin-19; mRNA Stability; migration; mortality; novel; paracrine; protective effect; receptor; response; transcription factor

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.

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 是一种新描述的 Th2（T 调节性）抗炎白细胞介素，在我们的研究之前，它被认为是炎症细胞特异性的。我们仍然是唯一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 病理生理学方面，并证明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中被诱导； 2- 在 VSMC 中添加 IL-19 可减少其迁移、增殖以及增殖和炎症蛋白的丰度； 3- IL-19 不抑制 NF-kB，但确实以 HuR 依赖性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 Hemeoxygenase-1 (HO-1) 的表达，并以 HO-1 依赖性方式减少血管活性氧 (ROS) 诱导的细胞凋亡。在本申请中，我们提供的初步数据表明，向喂食致动脉粥样硬化饮食的LDLR-/-小鼠中添加重组IL-19可显着且显着地减少动脉粥样硬化斑块，并且IL-19-/-小鼠对结扎损伤有加剧的反应。根据已发表的初步数据，我们假设这些保护作用有多种多效机制，并且特定目标旨在测试每种机制。在目标 1 中，我们将确定 IL-19 的缺乏是否会加剧，以及过度表达是否会减轻动脉粥样硬化。目标 2 将检验以下假设：IL-19 保护的一种机制主要是通过过继性免疫系统极化为 Th2 来促进的。目标 3 将检验以下假设：IL-19 动脉粥样硬化保护作用是通过白细胞-内皮细胞相互作用的减少和/或 IL-19 诱导 HO-1 表达介导的。目标 4 将确定 IL-19 如何降低炎症基因丰度的分子机制。该应用可能会改变范式，因为它将暗示 Th2 白细胞介素是一种由发炎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。它将确定这些细胞中抗炎途径的新分子机制和靶标。