Abstract 79: Interleukin-19 Reduces Leukocyte-Endothelial Cell Interactions

Abstract

Introduction Vascular endothelial cells (EC) actively participate in the pathogenesis of atherosclerosis by increasing expression of cell adhesion molecules which tether and adhere to leukocytes. The goal of the present study was to test the hypothesis that interleukin-19 (IL-19), an anti-inflammatory Th2 cytokine, can decrease expression of EC adhesion molecules and subsequently decrease leukocyte-endothelial cell interactions in vitro and in vivo. Methods and Results Cultured human coronary artery EC were pre-treated for various times with IL-19 (100 ng/ml) followed by stimulation with tumor necrosis factor-α (TNF-α; 10 ng/ml). IL-19 significantly reduced TNF-α-driven mRNA and protein abundance of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) (p<0.01). Surprisingly, IL-19 did not inhibit TNF-α-activation of the transcription factor NFκB. ICAM-1 and VCAM-1 transcript stability was significantly reduced in IL-19-treated EC (p<0.05). IL-19 treatment inhibited cytoplasmic localization of the mRNA stability factor HuR, and siRNA knock-down of HuR also decreased ICAM-1 and VCAM-1 transcript stability. IL-19 treatment of EC, but not treatment of monocytes, significantly reduced monocyte adhesion to EC monolayers (p<0.01). Leukocyte rolling and adhesion was quantitated in C57/B6 mice treated with a single systemic dose of IL-19 (10 ng/g) followed by TNF-α (400 ng) using intravital microscopy. IL-19 treatment resulted in a significant decrease (p<0.05) in TNF-α-driven leukocyte rolling and adhesion in vivo. Systemic administration of IL-19 (1.0ng/g/day) reduced CD68-positive cell infiltration into atherosclerotic plaque in LDLR -/- mice fed an atherogenic diet for 14 weeks (P<0.01). Conclusion These data are the first report that IL-19 can reduce leukocyte-endothelial cell interactions in vitro and in vivo, and suggest a reduction in HuR-mediated mRNA stability of ICAM-1 and VCAM-1 as a mechanism. These results suggest that IL-19 is an important negative regulator of vascular inflammatory diseases.