Cyclic Stretch Upregulates Production of Interleukin-8 and Monocyte Chemotactic and Activating Factor/Monocyte Chemoattractant Protein-1 in Human Endothelial Cells

From the Department of Cardiovascular Medicine, Kyoto University, Kyoto (M.O., A.M., Y.F., T.S., A.I., S.S.); the Department of Pharmacology, Cancer Research Institution, Kanazawa University, Kanazawa (K.M.); and the Department of Molecular Preventive Medicine, School of Medicine, University of Tokyo, Tokyo (K.M.), Japan.

Correspondence to Akira Matsumori, MD, PhD, Department of Cardiovascular Medicine, Kyoto University, 54 Kawaracho Shogoin, Sakyo-ku, Kyoto 606, Japan. E-mail amat{at}kuhp.kyoto-u.ac.jp

Abstract—In vivo, vascular walls are exposed to mechanical stretch, which may promote atherogenesis. This study was designed to investigate the effect of mechanical stretch on the production and gene expression of cytokines in endothelial cells (ECs) of human umbilical veins. ECs were cultured on flexible silicone membranes and exposed to cyclic mechanical stretch. Although the secretion levels of interleukin (IL)-1ß, tumor necrosis factor-, IL-6, granulocyte (G) -colony stimulating factor(CSF), G and macrophage (M) -CSF, and M-CSF were not affected by cyclic stretch over 24 hours, the levels of IL-8 and monocyte chemotactic and activating factor (MCAF)/monocyte chemoattractant protein-1 (MCP-1) were significantly increased by cyclic stretch. Northern blot analysis indicated that the mRNA levels of IL-8 and MCAF/MCP-1 were upregulated by cyclic stretch as a function of its intensity. Cytochalasin D, which disrupts the actin cytoskeleton, abolished the stretch-induced gene expression of IL-8 and MCAF/MCP-1. In contrast, neither inhibition of stretch-activated ion channels nor disruption of microtubules affected the induction of these chemokines by cyclic stretch. Northern blot analysis using enzyme inhibitors showed that phospholipase C, protein kinase C, and tyrosine kinase were involved in the stretch-induced gene expression of IL-8 and MCAF/MCP-1, whereas cAMP- or cGMP-dependent protein kinase was not. In conclusion, cyclic stretch enhanced the secretion and gene expression of IL-8 and MCAF/MCP-1 in a stretch-dependent fashion, and the integrity of the actin cytoskeleton and activities of phospholipase C, protein kinase C, and tyrosine kinase may be essential in the process of stretch-induced gene induction of IL-8 and MCAF/MCP-1.

Key Words: atherosclerosis • interleukin-8 • macrophage chemotactic and activating factor • monocyte chemoattractant protein-1 • hemodynamic forces

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