Simvastatin inhibits cytokine production and nuclear factor-kB activation in interleukin 1beta-stimulated synoviocytes from rheumatoid arthritis patients.
OBJECTIVE
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 micromol/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.
Lazzerini
P E
PE
Department of Clinical Medicine and Immunological Sciences, Division of Clinical Immunology, University of Siena, Italy. pietroenea@yahoo.it
Lorenzini
S
S
Selvi
E
E
Capecchi
P L
PL
Chindamo
D
D
Bisogno
S
S
Ghittoni
R
R
Natale
M R
MR
Caporali
F
F
Giuntini
S
S
Marcolongo
R
R
Galeazzi
M
M
Laghi-Pasini
F
F
D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004224:Diterpenes / Q000494:pharmacology; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology*; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
D004224:Diterpenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D019821:Simvastatin; C017338:geranylgeraniol; D008798:Mevalonic Acid