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Simvastatin Decreases IL-6 and IL-8 Production in Epithelial Cells

¹ Department of Periodontology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Sakuragaoka 8-35-1, Kagoshima 890-8544, Japan;
² Department of Periodontology, Showa University Dental School, Tokyo, Japan;
³ School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan;
⁴ Vascular Medicine Unit, Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; and
⁵ Department of Cardiovascular & Renal Medicine, Saga University Faculty of Medicine, Saga, Japan

^* corresponding author, kenjis{at}denta.hal.kagoshima-u.ac.jp

Many cardiovascular studies have suggested that 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors (statins) have anti-inflammatory effects independent of cholesterol lowering. As a chronic inflammatory disease, periodontitis shares some mechanisms with atherosclerosis. Since oral epithelial cells participate importantly in periodontal inflammation, we measured simvastatin effects on interleukin-6 and interleukin-8 production by cultured human epithelial cell line (KB cells) in response to interleukin-1. Simvastatin decreased production, an effect reversed by adding mevalonate or geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate. Simvastatin was found to reduce NF-B and AP-1 promoter activity in KB cells. Dominant-negative Rac1 severely inhibited interleukin-1-induced NF-B and AP-1 promoter activity. Our results may indicate an anti-inflammatory effect of simvastatin on human oral epithelial cells, apparently involving Rac1 GTPase inhibition.

KEY WORDS: simvastatin (3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitor) • pleiotropic effects • inflammatory cytokines • periodontitis • human oral epithelial cell