Statin inhibits interferon--induced expression of intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial and smooth muscle cells

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, known as statins, are widely used for primary and secondary prevention of coronary artery atherosclerosis. Pathogenesis of atherosclerosis is multistep processes where transendothelial migration of various leukocytes including monocytes is a crucial step. Interferon$-{\gamma}\;(IFN-{\gamma})$ contributes in this process by activating macrophages and T-lymphocytes, and by inducing adhesion molecules in vascular endothelial and smooth muscle cells. In this study we investigated the expression of intercellular cell adhesion molecule- 1 (ICAM-1) in transformed endothelial cell line ECV304 cells as influenced by lovastatin, tumor necrosis factor-${\alpha}\;(TNF-{\alpha})$ and $IFN-{\gamma}$. Results show that lovastatin suppresses expression of ICAM-1 by inhibiting the $IFN-{\gamma}-induced$ extracellular signal-regulated kinase (ERK) p44/p42-STAT1 signaling pathway. In cells treated with lovastatin and $IFN-{\gamma}$, ICAM-1 was expressed at a lower level than in cells treated with $IFN-{\gamma}$ alone. However, lovastatin does not reduce $TNF-{\alpha}$ induced expression of ICAM-1. A similar result was observed in cells treated with the MEKK inhibitor PD98059 and $IFN-{\gamma}$. Cis-acting DNA sequence elements were identified in the 5'-flanking region of the ICAM-1 promoter that mediate inhibition by lovastatin; these sequences map to the $IFN-{\gamma}$ activated site which also binds the STAT1 homodimer. However, lovastatin did not inhibit $IFN-{\gamma}-mediated$ induction of the Y701 phosphorylated form of STAT1. But lovastatin does inhibit the $IFN-{\gamma}-mediated $ phosphorylation of ERK1/ERK2 (T202/Y204) and S727 phosphorylation of STAT1. $TNF-{\alpha}$ does not induce phosphorylation of ERK1/ERK2 and S727 in ECV304 and smooth muscle cells. The results provide the evidences that statins may have beneficial effects by inhibiting $IFN-{\gamma}$ action in atherosclerotic process