The development of multiple vascular diseases ranging from atherosclerosis to transplant vasculopathy are inflammatory in nature. Although much is known about the deleterious effects of pro-inflammatory cytokines on vascular smooth muscle cells (VSMC) pathophysiology, we know very little about the direct protective effects of anti-inflammatory cytokines on VSMC. Our overall hypothesis is that IL -19 plays a protective role in the vascular response to injury by direct inhibitory effects on VSMC activation. IL-19 is a recently described member of the IL -10 family of anti-inflammatory cytokines. IL-19 expression is ascribed to be restricted to hematopoetic and inflammatory cells, where it has an anti-inflammatory effect. Nothing has been reported on the mechanism(s) of IL-19 effects, either in immune or vascular cells. We have found that;IL-19 is not expressed in quiescent VSMC or normal arteries, but is induced in VSMC by inflammatory cytokines and in arteries by injury;IL -19 is anti-proliferative for cultured, human coronary artery VSMC, induces activation of STAT-3;inhibits activation of signal transduction MAPK and expression of proliferative and inflammatory genes. IL -19 induces expression of the suppressor of cytokine signaling 5 (SOCS5), but inhibits expression and translocation of HuR, a stability factor which regulates decay of inflammatory and proliferative gene mRNA. IL-19 adenoviral gene transfer significantly reduces neointimal formation and VSMC proliferation in balloon angioplasty-injured rat carotid arteries. The overall goals of this application are designed to characterize the mechanism of IL -19 suppressive effects on VSMC and development of progression of intimal hyperplasia in response to vascular injury. We will test the hypothesis that STAT3 activation, SOCS5 expression, and HuR down-regulation are critical events in IL -19 mediated VSMC protection. We will test the hypothesis that IL-19 has protective effects on VSMC by decreasing expression of proliferative and inflammatory genes, and will define the mechanism(s) of these effects. We will test the hypothesis that IL -19 anti-restenotic effects in vivo are due at least in part by attenuation of inflammatory and proliferative gene expression, mediated by expression of SOCS5 and down regulation of HuR.

Public Health Relevance

Cardiovascular disease is the number one cause of mortality in the United States and places an enormous medical and economic burden on our society. This application will address the novel concept of direct beneficial effects of anti- inflammatory cytokines on vascular pathophysiology.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Tolunay, Eser
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Temple University
Schools of Medicine
United States
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Richards, James; Gabunia, Khatuna; Kelemen, Sheri E et al. (2015) Interleukin-19 increases angiogenesis in ischemic hind limbs by direct effects on both endothelial cells and macrophage polarization. J Mol Cell Cardiol 79:21-31
Ellison, Stephen; Gabunia, Khatuna; Richards, James M et al. (2014) IL-19 reduces ligation-mediated neointimal hyperplasia by reducing vascular smooth muscle cell activation. Am J Pathol 184:2134-43
England, Ross N; Preston, Kyle J; Scalia, Rosario et al. (2013) Interleukin-19 decreases leukocyte-endothelial cell interactions by reduction in endothelial cell adhesion molecule mRNA stability. Am J Physiol Cell Physiol 305:C255-65
Autieri, Michael V (2013) Increasing our IQ of vascular smooth muscle cell migration with IQGAP1. Focus on ""IQGAP1 links PDGF receptor-? signal to focal adhesions involved in vascular smooth muscle cell migration: role in neointimal formation after vascular injury"". Am J Physiol Cell Physiol 305:C579-80
Ellison, Stephen; Gabunia, Khatuna; Kelemen, Sheri E et al. (2013) Attenuation of experimental atherosclerosis by interleukin-19. Arterioscler Thromb Vasc Biol 33:2316-24
Gabunia, Khatuna; Ellison, Stephen P; Singh, Harrinder et al. (2012) Interleukin-19 (IL-19) induces heme oxygenase-1 (HO-1) expression and decreases reactive oxygen species in human vascular smooth muscle cells. J Biol Chem 287:2477-84
Jain, Surbhi; Gabunia, Khatuna; Kelemen, Sheri E et al. (2011) The anti-inflammatory cytokine interleukin 19 is expressed by and angiogenic for human endothelial cells. Arterioscler Thromb Vasc Biol 31:167-75
Takaguri, Akira; Kimura, Keita; Hinoki, Akinari et al. (2011) A disintegrin and metalloprotease 17 mediates neointimal hyperplasia in vasculature. Hypertension 57:841-5
Gabunia, Khatuna; Jain, Surbhi; England, Ross N et al. (2011) Anti-inflammatory cytokine interleukin-19 inhibits smooth muscle cell migration and activation of cytoskeletal regulators of VSMC motility. Am J Physiol Cell Physiol 300:C896-906
Hinoki, Akinari; Kimura, Keita; Higuchi, Sadaharu et al. (2010) p21-activated kinase 1 participates in vascular remodeling in vitro and in vivo. Hypertension 55:161-5

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