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.
Peripheral vascular disease is a significant medical and socioeconomic problem contributing to mortality of multiple diseases including myocardial infarction, diabetes, and peripheral vascular disease. Interleukin-19 (IL-19) is a newly described anti- inflammatory interleukin expressed in ischemic tissue and angiogenic effects in endothelial cells. The overall goal of this application is to test the hypothesis that IL-19 can promote neovascularization and perfusion of ischemic tissue.
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