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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

View larger version (16K): [in a new window]   Figure 1. Dose-dependent effects of simvastatin on KB cells. (A) Cellular expression of IL-6 and IL-8 is shown in cultures after treatment with the indicated concentrations of simvastatin for 7 hrs, and/or IL-1 (1 ng/mL) for the last 5 of these hrs. Data are expressed as means ± SD (n = 4). *P < 0.01 and **P < 0.001 vs. control (treated with IL-1). (B) Evaluation of cytotoxicity from simvastatin according to release of LDH into medium was carried out after 24 hrs of culture. LC, low control (medium alone); HC, high control (1% Triton X100).

View larger version (20K): [in a new window]   Figure 2. Reversal of inhibitory effect of simvastatin on KB cells by co-treatment with downstream metabolites of HMG-CoA reductase. (A) Inhibitory effects of simvastatin (10–6 M) on KB cells were reversed by co-treatment with mevalonate (10–4 M) or GGPP (5 x 10–6 M), but not with FPP (5 x 10–6 M). Data are expressed as means ± SD (n = 4). *P < 0.001 vs. control (treated with IL-1). (B) Schematic representation of the mevalonate pathway. Statins block conversion of HMG-CoA to mevalonate. This leads to reduced synthesis of cholesterol and decreased prenylation of proteins such as small GTPases. Isopentenyl-PP, isopentenyl pyrophosphate; Geranyl-PP, geranyl pyrophosphate.

View larger version (8K): [in a new window]   Figure 3. Suppression of NF-B and AP-1 activity in IL-1-stimulated KB cells by simvastatin (10–6 M). KB cells were transiently co-transfected with pNF-B-luc or pAP-1-luc, together with pCMV-ßgal. The cells were analyzed 48 hrs later, with five-hour stimulation with IL-1 (1 ng/mL). All results were normalized for transfection efficiency using expression of ß-galactosidase. Data are expressed as means ± SD (n = 4). *P < 0.001 vs. control (treated with IL-1).

View larger version (15K): [in a new window]   Figure 4. Effects of Rho family GTPases on IL-1-mediated transactivation of NF-B and AP-1. (A) IL-1-induced NF-B and AP-1 promoter activity of the transient transfectants of N17Rac1 was greatly inhibited, and IL-1-induced NF-B and AP-1 promoter activities of transiently transfected cells (N17Cdc42 and N19RhoA) also were inhibited. Mock, transient transfectants of empty vector. Data represent means ± SD (n = 4). *P < 0:01 and **P < 0.001 vs. control (mock with IL-1). (B) Model depicting contributions of Rho family GTPases to NF-B and AP-1 activation by IL-1. Rho, Rho family GTPases; GG-Rho, geranylgeranylated Rho family GTPases.