HMG-CoA reductase inhibitor cerivastatin inhibits interleukin-6 expression and secretion in human adipocytes.
Human adipose tissue is a main contributor to plasma levels of pro-inflammatory cytokine IL-6. How IL-6 expression is regulated in adipocytes remains unclear. In the current study, we investigated the effect of the HMG-CoA reductase inhibitor, cerivastatin, on the production of IL-6 from cultured human adipocytes. Cerivastatin reduced both IL-6 mRNA and secretion in a dose- and time-dependent manner. The inhibitory effect on IL-6 mRNA was prevented by the intermediates of the cholesterol synthesis pathway, mevalonate and geranyl-geranyl-phyrophosphate (GGPP) but not by farnesyl-pyrophosphate. This suggests the involvement of geranylgeranyl-modified intermediates in the effect of cerivastatin on IL-6. Moreover, cerivastatin induced an inactivation of the phosphorylation of the p65 subunit of NFkappaB which was prevented by GGPP. Our data suggest that cerivastatin exerts an anti-inflammatory effect by down-regulating IL-6 levels in adipocytes, which seems to be mediated by reduced production of GGPP and interference with the NFkappaB pathway.
van Harmelen
V
V
Deutsches Diabetes-Forschungsinstitut, Düsseldorf, Germany.
Skurk
T
T
Röhrig
K
K
Hauner
H
H
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000328:Adult; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics; D008798:Mevalonic Acid / Q000494:pharmacology; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051996:Transcription Factor RelA; D000093242:Interleukin-6 Inhibitors
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D008798:Mevalonic Acid; D016328:NF-kappa B; D011725:Pyridines; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D000093242:Interleukin-6 Inhibitors; C086276:cerivastatin