Mechanisms of Th2 interleukin-driven angiogenesis

Th2白细胞介素驱动的血管生成机制

• 批准号: 8666808
• 负责人: MICHAEL V AUTIERI
• 金额: $ 38.18万
• 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/8666808
• 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介素19（IL-19）是一种抗炎，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，（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。炎性和抗炎细胞因子都参与伤口愈合和新血管化，但是抗炎性细胞因子在血管生成中的作用和这些过程之间的串扰仍然没有表征。与我们先前的工作相反，IL-19抑制了血管平滑肌细胞（VSMC）迁移和增殖，我们最近报道了令人惊讶的发现，IL-19具有对人内皮细胞（EC）具有有效的促血管生成作用。在正常的EC中未检测到IL-19，但在人类血管生成组织的毛细血管中以EC表示。 IL-19具有促EC的有丝分裂和趋化性，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，体内PECAM1阳性微血管。 IL-19可以在EC中诱导血管生成基因表达。 IL-19效应与VEGF和BFGF无关，因为均不能诱导IL-19的表达，而IL-19不能诱导这两个表达。 BFGF和VEGF的中和不影响IL-19活性，这表明一种新型Th2诱导的途径刺激EC激活和血管生成。 IL-19可以使人类巨噬细胞对M2两极，“伤口愈合”表型，并在巨噬细胞中诱导血管生成基因表达。 IL-19的表达和功能与促炎性抗血管生成细胞因子IL-12相互调节。这些初步和已发表的数据驱动了以下假设：IL-19是一种具有多个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中的血液流动，主要效应细胞是内皮细胞或M2巨噬细胞，哪些可溶因子介导IL-19的效应，以及IL-19的分子机制和介体在EC和VSMC中的不同效应。 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 IL-20受体亚基的差异表达与EC相比，VSMC中IL-19的多效效应。该应用可能会改变范式，因为它将暗示Th2白细胞介素作为一种新型的抗炎，促血管生成细胞因子，该因子被发炎的居民血管细胞表达，以促进新生血管形成。