Simvastatin inhibits production of interleukin 6 (IL-6) and IL-8 and cell proliferation induced by tumor necrosis factor-alpha in fibroblast-like synoviocytes from patients with rheumatoid arthritis.
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-alpha (TNF-alpha) in fibroblast-like synoviocytes (FLS) obtained from RA patients undergoing joint replacement therapy.


METHODS
RA FLS were cultured with or without 0.05-10 microM 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-alpha 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-alpha. 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.


CONCLUSIONS
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.
Yokota
Kazuhiro
K
Division of Rheumatology and Applied Immunology, Department of Medicine, Saitama Medical School, Iruma-gun, Saitama, Japan.
Miyazaki
Takashi
T
Hirano
Motoharu
M
Akiyama
Yuji
Y
Mimura
Toshihide
T
D001172:Arthritis, Rheumatoid / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004338:Drug Combinations; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008798:Mevalonic Acid / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000093242:Interleukin-6 Inhibitors
D004338:Drug Combinations; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D016209:Interleukin-8; D008798:Mevalonic Acid; D011106:Polyisoprenyl Phosphates; D012333:RNA, Messenger; D019821:Simvastatin; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C002963:geranylgeranyl pyrophosphate