Mechanisms of Th2 interleukin-driven angiogenesis

Th2白细胞介素驱动的血管生成机制

• 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
• 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

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细胞介素-19（IL-19）（一种抗炎性Th 2白细胞介素）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，以研究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。炎性和抗炎性细胞因子都参与伤口愈合和新血管形成，但抗炎性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。与我们以前的工作表明IL-19抑制血管平滑肌细胞（VSMC）迁移和增殖相反，我们最近报道了令人惊讶的发现，IL-19对人内皮细胞（EC）具有强效促血管生成作用。IL-19在正常EC中未检测到，但在人血管生成组织的毛细血管中的EC中表达。IL-19对EC具有促有丝分裂和趋化作用，促进细胞铺展，并激活MAPK和Rac 1。IL-19促进主动脉环中的微血管形成和体内PECAM 1阳性微血管。IL-19可诱导EC中血管生成基因的表达。IL-19的作用不依赖于VEGF和bFGF，因为两者都不能诱导IL-19的表达，并且IL-19也不能诱导两者的表达。bFGF和VEGF的中和不影响IL-19的活性，这表明一种新的Th 2诱导的途径来刺激EC活化和血管生成。IL-19可使人巨噬细胞向M2型转化，即“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性抗血管生成细胞因子IL-12相互作用并调节IL-12。这些初步和已发表的数据推动了IL-19是一种具有多种效应细胞的新型血管生成细胞因子的假设。需要确定的是，如果IL-19可以恢复缺血组织中的血流，如果主要的效应细胞是内皮细胞或M2巨噬细胞，什么可溶性因子介导IL-19的作用，以及IL-19在EC和VSMC中的差异作用的分子机制和介质。我们将确定IL-19的缺乏是否减弱，IL-19的过表达是否促进缺血组织中的血管生成并恢复血流，IL-19对血管生成的调节是否通过对血管细胞的直接作用或通过巨噬细胞M2极化而促进，将鉴定和表征IL-19驱动的体内血管生成所必需的IL-19诱导因子，并验证了IL-20受体亚单位的差异表达解释了IL-19在VSMC中与EC相比的多效性效应的假设。这种应用是潜在的范式改变，因为它将涉及一种Th 2白细胞介素作为一种新的抗炎，促血管生成的细胞因子，由发炎的常驻血管细胞表达，以促进新血管形成。