Mechanisms of Th2 interleukin-driven angiogenesis

Th2白细胞介素驱动的血管生成机制

基本信息

批准号：
8508007
负责人：
MICHAEL V AUTIERI
金额：
$ 36.89万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8508007
关键词：
Accounting Affect Agonist Angiogenic Factor Anti-Inflammatory Agents Anti-inflammatory Area Attenuated Back Biology Blood Vessels Blood capillaries Blood flow Bone Marrow Transplantation Cells Data Diabetes Mellitus Disease Effector Cell Endothelial Cells Fibroblast Growth Factor Fibroblast Growth Factor 2 Functional disorder Gene Expression Goals Human Inflammatory Injection of therapeutic agent Interleukin-12 Interleukins Investments Isolated limb perfusion Laboratories Leucocytic infiltrate MAP Kinase Gene Mediating Mediator of activation protein Medical Microarray Analysis Molecular Mus Myocardial Infarction PECAM1 gene Pathway interactions Perfusion Peripheral Vascular Diseases Phenotype Process Publishing Receptor Signaling Regulation Reporting Role Signal Transduction Small Interfering RNA Smooth Muscle Myocytes Source Testing Tissues Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascularization Wild Type Mouse Work Wound Healing angiogenesis cDNA Arrays capillary cell growth cytokine improved in vivo indexing interleukin 20 interleukin-19 knock-down macrophage matrigel migration mortality neovascularization novel public health relevance receptor socioeconomics vascular smooth muscle cell migration

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this application is to demonstrate that Interleukin-19 (IL-19), an anti-inflammatory, Th2 interleukin, can drive angiogenesis and improve perfusion of ischemic tissue. 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. Both inflammatory and anti- inflammatory cytokines participate in wound healing and neo-vascularization, but the role of anti- inflammatory cytokines in angiogenesis and the cross-talk between these processes remain under characterized. In contrast to our previous work indicating that IL-19 suppresses vascular smooth muscle cells (VSMC) migration and proliferation, we have recently reported the surprising finding that IL-19 has potent pro-angiogenic effects on human endothelial cells (EC). IL-19 is not detected in normal EC but is expressed in EC in capillaries in human angiogenic tissue. IL-19 is mitogenic and chemotactic for EC, promotes cell spreading, and activates MAPK and Rac1. IL-19 promotes microvessel formation in aortic rings, and PECAM1-positive microvessels in vivo. IL-19 can induce angiogenic gene expression in EC. IL-19 effects are independent of VEGF and bFGF, as neither can induce IL-19 expression, and IL-19 cannot induce expression of either. Neutralization of bFGF and VEGF does not affect IL-19 activity, suggesting a novel, Th2-induced pathway to stimulate EC activation and angiogenesis. IL-19 can polarize human macrophage to the M2, "wound healing" phenotype, and induce angiogenic gene expression in macrophage. IL-19 expression and function is reciprocal to and regulates the pro- inflammatory anti-angiogenic cytokine IL-12. These preliminary and published data have driven the hypothesis that IL-19 is a novel vasculogenic cytokine with multiple effector cells. What needs to be determined is if IL-19 can restore blood flow in ischemic tissue, if the major effector cell is endothelial cells or the M2 macrophage, what soluble factors mediate IL-19 effects, and the molecular mechanisms and mediators of IL-19 differential effects in EC and VSMC. We will determine if absence of IL-19 attenuates, and if over expression of IL-19 promotes angiogenesis and restores blood flow in ischemic tissue, if IL-19 regulation of angiogenesis is facilitated by direct effects on vascular cells, or by macrophage M2 polarization, will identify and characterize IL-19 inducible factors necessary for IL-19- driven angiogenesis in vivo, and test the hypothesis that differential expression of IL-20 receptor subunits account for pleiotropic effects of IL-19 in VSMC compared with EC. This application is potentially paradigm-changing as it will implicate a Th2 interleukin as a novel anti-inflammatory, pro-vasculogenic cytokine expressed by inflamed resident vascular cells to promote neovascularization.

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)（一种抗炎 Th2 白介素）可以驱动血管生成并改善缺血组织的灌注。 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。炎症和抗炎细胞因子均参与伤口愈合和新血管形成，但抗炎细胞因子在血管生成中的作用以及这些过程之间的相互作用仍不清楚。与我们之前表明 IL-19 抑制血管平滑肌细胞 (VSMC) 迁移和增殖的工作相反，我们最近报道了令人惊讶的发现，即 IL-19 对人内皮细胞 (EC) 具有有效的促血管生成作用。 IL-19 在正常 EC 中未检测到，但在人血管生成组织毛细血管的 EC 中表达。 IL-19 对 EC 具有促有丝分裂和趋化作用，促进细胞扩散，并激活 MAPK 和 Rac1。 IL-19 促进主动脉环中的微血管形成以及体内 PECAM1 阳性微血管的形成。 IL-19可以诱导EC中血管生成基因的表达。 IL-19 的作用独立于 VEGF 和 bFGF，因为两者都不能诱导 IL-19 表达，并且 IL-19 不能诱导其中任何一个的表达。 bFGF 和 VEGF 的中和不影响 IL-19 活性，表明 Th2 诱导的新途径可刺激 EC 激活和血管生成。 IL-19 可以将人巨噬细胞极化至 M2（“伤口愈合”表型），并诱导巨噬细胞中血管生成基因的表达。 IL-19 的表达和功能与促炎抗血管生成细胞因子 IL-12 互相关，并对其进行调节。这些初步和已发表的数据推动了这样的假设：IL-19 是一种具有多种效应细胞的新型血管生成细胞因子。需要确定的是IL-19是否可以恢复缺血组织的血流、主要效应细胞是内皮细胞还是M2巨噬细胞、哪些可溶性因子介导IL-19的作用以及IL-19的分子机制和介质EC 和 VSMC 的不同影响。我们将确定 IL-19 的缺失是否会减弱，IL-19 的过度表达是否会促进血管生成并恢复缺血组织中的血流，IL-19 对血管生成的调节是否是通过对血管细胞的直接作用或巨噬细胞 M2 极化来促进的，将鉴定和表征 IL-19 驱动的体内血管生成所需的 IL-19 诱导因子，并测试 IL-20 受体亚基的差异表达解释的假设与 EC 相比，IL-19 对 VSMC 的多效性作用。该应用可能会改变范式，因为它将暗示 Th2 白细胞介素是一种新型抗炎、促血管生成细胞因子，由发炎的常驻血管细胞表达，以促进新血管形成。