Anti-inflammatory effect of simvastatin in human oral epithelial cells

Objectives: Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor, are widely used for treatment of hypercholesterolemia. Recently, extensive researches suggest that the clinical benefits of statins could be related to anti-inflammatory properties, an improvement in endothelial dysfunction, a reduction in blood thrombogenicity, and immunomodulatory actions. These cholesterol-lowering independent, pleiotropic, effects are related with the inhibition of isoprenoid synthesis, which serve as a lipid attachment for small G proteins implicated in intracellular signaling. These pleiotropic effects of statins may be beneficial to treat periodontitis, manifesting increased proinflammatory factors such as IL-1b, IL-6, and TNF- a. It is known that the oral epithelial cell is known to play an important role for the immune response in periodontitis. The purpose of this study, therefore, is to identify the anti-inflammatory effect of simvastatin on the human oral epithelium cell line (KB) stimulated with IL-1 a. Methods: KB cells were stimulated by recombinant human IL-1a at the concentration of 1ng/mL for 5 h, in the presence of simvastatin (0, 10^-9 -10^-5 M). We analyzed cytokine expression (IL-8, IL-1b, IL-6, IL-10, TNF-a, IL-12p70) using Cytometric Bead Array (CBA: BD Pharmingen, San Diego, CA). We also evaluated the NF-kB and AP-1 promoter activity using luciferase reporter assay. Results: Simvastatin decreased the IL-6 and IL-8 production in KB culture in dose dependent manner (0, 10^-9 -10^-6 M). This decrease was reversed by addition of L-mevalonate and GGPP, but not FPP. Furthermore, simvastatin decreased the NF-kB and AP-1 promoter activity in KB cells. Conclusion: Our results indicate that simvastatin has an anti-inflammatory effect on KB cells by pleiotropic mechanism. It is known that FPP and GGPP mediate the post-translational modification (prenylation) of Ras and Rho respectively. Hence Rho, but not Ras, could be implicated in this beneficial effect of simvastatin in human oral epithelial cell.