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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:725.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Human IL-8 Regulates Smooth Muscle Cell VCAM-1 Expression in Response to Endothelial Cells Exposed to Atheroprone Flow

Nicole E. Hastings; Ryan E. Feaver; Monica Y. Lee; Brian R. Wamhoff; Brett R. Blackman

From the Department of Biomedical Engineering (N.E.H., R.E.F., M.Y.L., B.R.W., B.R.B.), the Department of Medicine, Cardiovascular Division (M.Y.L., B.R.W.), the Robert M. Berne Cardiovascular Research Center (N.E.H., R.E.F., M.Y.L., B.R.W., B.R.B.), and the Laboratory of Atherogenesis (N.E.H., R.E.F., M.Y.L., B.R.W., B.R.B.), University of Virginia, Charlottesville.

Correspondence to Brett R. Blackman, PhD, Department of Biomedical Engineering, PO Box 800759, Charlottesville, VA 22908. E-mail bblackman{at}virginia.edu

Objective— Interleukin-8 (IL-8) is a soluble human-specific chemokine implicated in the development of the chronic inflammatory disease atherosclerosis. Recently, we showed that atheroprone hemodynamics induced IL-8 secretion from endothelial cells (ECs) concurrent with increased EC/smooth muscle cell (SMC) VCAM-1 expression in a human hemodynamic coculture model. Despite an IL-8 association with inflammation, we show here that blocking IL-8 activity during atheroprone flow resulted in increased levels of EC/SMC VCAM-1 expression. We tested the hypothesis that IL-8 limits SMC VCAM-1 expression in response to inflammatory stimuli, either atheroprone flow or cytokine interleukin-1β (IL-1β) addition.

Methods and Results— Atheroprone flow increased monocyte adhesion in both EC/SMCs, concurrent with the induction of VCAM-1 protein. VCAM-1 antisera attenuated this response. IL-1β upregulated VCAM-1 in SMCs by 3-fold, a response inhibited by the addition of IL-8 at 24 hours. Neither IL-1β nor IL-8 induced proliferation or migration. Neutralization of the IL-8 receptor, CXCR2, further induced VCAM-1 in the presence of IL-1β, and phospho-p38 was required for NF-B activation and VCAM-1 expression. Additionally, IL-8 reduced p38 activation and NF-B activity induced by IL-1β alone.

Conclusions— Together, these findings provide evidence for a novel role whereby IL-8 limits the inflammatory response in ECs/SMCs via VCAM-1 modulation.

The human chemokine interleukin-8 (IL-8) is implicated in atherosclerosis development. Contrary to our hypothesis that IL-8 has proinflammatory effects on the vasculature, we show herein that IL-8 limits SMC VCAM-1 expression in response to inflammatory stimuli by reducing activation of p38 and NF-B, and thereby decreasing VCAM-1 expression and suppressing monocyte adhesion.

Key Words: endothelial • smooth muscle • interleukin-8 • VCAM-1 • hemodynamics