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KAZUHIRO YOKOTA, TAKASHI MIYAZAKI, MOTOHARU HIRANO, YUJI AKIYAMA, and TOSHIHIDE MIMURA

ABSTRACT.

Objective. Rheumatoid arthritis (RA) is a chronic inflammatory disease in which the synovial environment is characterized by intense immunological activity. Evidence suggests that statins modulate immune functions and may have a beneficial effect on patients with RA. We investigated whether simvastatin could inhibit the expression of interleukin 6 (IL-6) and IL-8 and cell proliferation induced by tumor necrosis factor-a (TNF-a) in fibroblast-like synoviocytes (FLS) obtained from RA patients undergoing joint replacement therapy.

Methods. RA FLS were cultured with or without 0.05–10 µM simvastatin for 12 h. Cytokine mRNA expression and secretion levels were detected using real-time PCR and ELISA, respectively. Cell proliferation of FLS induced by TNF-a was determined by MTT assay.

Results. Real-time PCR analysis revealed that the levels of IL-6 and IL-8 mRNA expressed by FLS were reduced by simvastatin in a dose-dependent manner. Levels of IL-6 and IL-8 in FLS culture supernatants were decreased by simvastatin in a time-dependent and dose-dependent manner. MTT assay revealed that simvastatin could inhibit proliferation of FLS induced by TNF-a. These effects of simvastatin on IL-6 and IL-8 production and cell proliferation were reversed in the presence of mevalonic acid or geranylgeranyl-pyrophosphate, but not with farnesyl-pyrophosphate.

Conclusion. Our results suggest that the beneficial effect of simvastatin in RA patients may involve inhibition of IL-6 and IL-8 production, as well as reduction of cell proliferation. (J Rheumatol 2006;33:463-71)

Key Indexing Terms:

FIBROBLAST-LIKE SYNOVIOCYTES
INTERLEUKIN 6
3-HYDROXY-3-METHYLGLUTARYL CO-ENZYME A REDUCTASE INHIBITOR
POLYMERASE CHAIN REACTION
INTERLEUKIN 8

From the Division of Rheumatology and Applied Immunology, Department of Medicine; and the Department of Health Science and Preventive Medicine, Saitama Medical School, Saitama, Japan.

K. Yokota, MD; M. Hirano, MD; Y. Akiyama, MD, PhD; T. Mimura, MD, PhD, Division of Rheumatology and Applied Immunology, Department of Medicine; T. Miyazaki, PhD, Department of Health Science and Preventive Medicine, Saitama Medical School.

Address reprint requests to Dr. T. Mimura, Division of Rheumatology and Applied Immunology, Department of Medicine, Saitama Medical School, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan. E-mail: toshim@saitama-med.ac.jp

Accepted for publication October 19, 2005.