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

• Published in: Experimental & molecular medicine 2002, 34(6), , pp.451-461
• Main Authors: Chung, Hyo Kyun, Lee, In Kyu, Kang, Hyokyung, Suh, Jae Mi, Kim, Ho, Park, Ki Cheol, Kim, Dong Wook, Kim, Young Kun, Ro, Heung Kyu, Shong, Minho
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; DNA-Binding Proteins - metabolism; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Gene Expression Regulation - drug effects; Intercellular Adhesion Molecule-1 - genetics; Intercellular Adhesion Molecule-1 - metabolism; Interferon-gamma - antagonists & inhibitors; Interferon-gamma - pharmacology; Lovastatin - pharmacology; Mitogen-Activated Protein Kinases - metabolism; Myocytes, Smooth Muscle - cytology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Phosphorylation - drug effects; Promoter Regions, Genetic - genetics; Rats; Recombinant Proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; STAT1 Transcription Factor; Trans-Activators - metabolism; Tumor Necrosis Factor-alpha - pharmacology; 생화학
• ISSN: 1226-3613; 2092-6413; 2092-6413
• DOI: 10.1038/emm.2002.63

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