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Interleukin-19（IL-19）是TH2抗炎性白细胞介素，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，（调节）抗炎白细胞介素，直到我们的工作一直归因于炎症细胞特异性。我们仍然是研究该白介素在血管生物学中的作用的唯一实验室，尤其是在EC和VSMC病理生理学方面，并证明这些作用的分子机制。我们以前报道了； 1- IL-19在正常动脉中无法检测到，但在人类动脉粥样硬化病变中的EC和VSMC中诱导。 2-在VSMC中添加IL-19可以减少其迁移，增殖和增生和炎性蛋白的丰度； 3- IL-19不抑制NF-KB，但确实以Hur依赖性方式降低了炎症和增生性mRNA转录的稳定性。 4- IL-19诱导血管和细胞保护蛋白血红素氧酶-1（HO-1）的表达，并以HO-1依赖性方式降低由血管活性氧（ROS）诱导的凋亡。在此应用中，我们介绍了初步数据，表明在LDLR - / - 小鼠中添加重组IL-19，显着添加了动脉粥样硬化饮食，并大大降低了动脉粥样硬化的斑块，而IL-19 - / - 小鼠对结扎损伤的反应恶化。基于已发布和初步数据，我们假设这些保护作用有多种，多效机制，并且特定的目的旨在测试这些机制中的每一种。在AIM 1中，我们将确定IL-19的不存在加重，是否过度表达会减弱动脉粥样硬化。 AIM 2将检验以下假设：IL-19保护的一种机制主要是通过收养的免疫系统极化促进的。 AIM 3将检验以下假设：IL-19的动脉保护是通过白细胞 - 内皮细胞相互作用的降低和/或IL-19诱导HO-1表达介导的。 AIM 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白细胞介素作为由发炎的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型分子机制和靶标。