Exp Mol Med.  2002 Dec;34(6):451-461.

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

• Chung HK
• Lee IK
• Kang HK
• Suh JM
• Kim H
• Park KC
• Kim DW
• Kim YK
• Ro HK
• Shong MH

Abstract

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

Keyword

arteriosclerosis; endothelium; vascular; interferon type II; mitogen-activated protein kinases; p42 MAP kinase

MeSH Terms

Animals
Cell Line
DNA-Binding Proteins/metabolism
Endothelium, Vascular/cytology/*drug effects/metabolism
Gene Expression Regulation/*drug effects
Intercellular Adhesion Molecule-1/genetics/*metabolism
Interferon Type II/*antagonists & inhibitors/*pharmacology
Lovastatin/*pharmacology
Mitogen-Activated Protein Kinases/metabolism
Myocytes, Smooth Muscle/cytology/*drug effects/metabolism
Phosphorylation/drug effects
Promoter Regions (Genetics)/genetics
RNA, Messenger/genetics/metabolism
Rats
Recombinant Proteins
Trans-Activators/metabolism
Tumor Necrosis Factor/pharmacology