Simvastatin inhibits cytokine production and nuclear factor-kB activation in interleukin 1β-stimulated synoviocytes from rheumatoid arthritis patients

Clinical and Experimental Rheumatology

S. Giuntini¹  R. Ghittoni¹  S. Lorenzini¹  F. Caporali¹  F. Laghi-Pasini¹  M.R. Natale¹  S. Bisogno¹  R. Marcolongo¹  M. Galeazzi¹  P.E. Lazzerini¹  E. Selvi¹  P.L. Capecchi¹  D. Chindamo¹ 

关键词: Simvastatin;    rheumatoid arthritis;    interleukin-6;    interleukin-8;    NF-kB;    interleukin-1;    inflammation;    synoviocytes.;   

DOI  :  

学科分类：医学（综合）

来源: Pacini Editore SpA

【 摘 要 】

OBJECTIVES:Recent studies demonstrated in vivo the effectiveness of statins in reducing the inflammatory response in rheumatic diseases, and still more recently, simvastatin has been reported to inhibit in vitro IL-6 and IL-8 production by unstimulated fibroblast-like-synoviocytes (FLS) from rheumatoid arthritis (RA) patients. However, no data are available on the effect of statins on the production of these cytokines induced by IL-1, which plays a crucial role in joint inflammation in the course of active RA in vivo.METHODS:In 12 RA patients, synovial tissue specimens were taken to obtain cultures of FLS. Cultures were incubated with IL-1 ± simvastatin (5-50 µmol/l), and IL-6 and IL-8 production was evaluated (ELISA), also following the addition of mevalonate and its isoprenoid derivatives. Moreover, nuclear factor-kB (NF-kB) activation (immunocytochemistry and Western Blot analysis) were also evaluated.RESULTS:Culture incubation with IL-1 produced a dramatic increase (up to 40-fold) in cytokine production with respect to unstimulated cells. Simvastatin significantly inhibited (about 20%) IL-6 and IL-8 production from IL-1-stimulated FLS. This effect was completely reverted by the concomitant incubation with mevalonate or geranylgeraniol (but not farnesol or squalene). Moreover, simvastatin produced a clear-cut inhibition of IL-1-induced NF-kB activation.CONCLUSIONS:Simvastatin significantly inhibits the production of IL-6 and IL-8 also in IL-1-stimulated FLS, even though to a lesser extent than in unstimulated cells, via a HMG-CoA-reductase block with an interference in prenylation process and NF-kB activation. Our results further support the rationale for the use of statins in the treatment of rheumatoid synovitis.

【 授权许可】

Unknown