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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Vascular Cell and Molecular Biology Study Section (VCMB)
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Gao, Yunling
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Temple University
Schools of Medicine
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Ray, Mitali; Gabunia, Khatuna; Vrakas, Christine N et al. (2018) Genetic Deletion of IL-19 (Interleukin-19) Exacerbates Atherogenesis in Il19-/-×Ldlr-/- Double Knockout Mice by Dysregulation of mRNA Stability Protein HuR (Human Antigen R). Arterioscler Thromb Vasc Biol 38:1297-1308
Autieri, Michael V (2018) IL-19 and Other IL-20 Family Member Cytokines in Vascular Inflammatory Diseases. Front Immunol 9:700
Ray, Mitali; Autieri, Michael V (2017) Regulation of pro- and anti-atherogenic cytokines. Cytokine :
Gabunia, Khatuna; Herman, Allison B; Ray, Mitali et al. (2017) Induction of MiR133a expression by IL-19 targets LDLRAP1 and reduces oxLDL uptake in VSMC. J Mol Cell Cardiol 105:38-48
Herman, Allison B; Autieri, Michael V (2017) Inflammation-regulated mRNA stability and the progression of vascular inflammatory diseases. Clin Sci (Lond) 131:2687-2699
Bruns, Danielle R; Ghincea, Alexander R; Ghincea, Christian V et al. (2017) Interleukin-19 is cardioprotective in dominant negative cyclic adenosine monophosphate response-element binding protein-mediated heart failure in a sex-specific manner. World J Cardiol 9:673-684
Trappanese, Danielle M; Sivilich, Sarah; Ets, Hillevi K et al. (2016) Regulation of mitogen-activated protein kinase by protein kinase C and mitogen-activated protein kinase phosphatase-1 in vascular smooth muscle. Am J Physiol Cell Physiol 310:C921-30
Kako, Farah; Gabunia, Khatuna; Ray, Mitali et al. (2016) Interleukin-19 induces angiogenesis in the absence of hypoxia by direct and indirect immune mechanisms. Am J Physiol Cell Physiol 310:C931-41
Autieri, Michael V (2016) Adipose inflammation at the heart of vascular disease. Clin Sci (Lond) 130:2101-2104
Gabunia, Khatuna; Ellison, Stephen; Kelemen, Sheri et al. (2016) IL-19 Halts Progression of Atherosclerotic Plaque, Polarizes, and Increases Cholesterol Uptake and Efflux in Macrophages. Am J Pathol 186:1361-74

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