HMG-CoA reductase inhibitor simvastatin inhibits proinflammatory cytokine production from murine mast cells.
BACKGROUND
Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a key rate-limiting enzyme in the mevalonate pathway. Accumulating data suggest that statins exhibit anti-inflammatory effects on a number of experimental models including experimental autoimmune encephalomyelitis and antigen-induced allergic airway inflammation. However, the mechanism underlying the anti-inflammatory effect of statins is still largely unknown. In this study, we examined the effect of a representative statin, simvastatin, on proinflammatory cytokine production from murine mast cells.


METHODS
Bone marrow-derived mast cells (BMMCs) were stimulated with lipopolysaccharide (LPS) in the presence or absence of simvastatin, and TNF-alpha and IL-6 production from BMMCs was evaluated at mRNA and protein levels. The effect of simvastatin on the expression of tristetraprolin, an RNA-binding protein that promotes decay of TNF-alpha mRNA, was evaluated.


RESULTS
Incubation of BMMCs with simvastatin resulted in the inhibition of LPS-induced TNF-alpha production at both mRNA and protein levels. Simvastatin also inhibited IL-6 production from LPS-stimulated BMMCs. However, simvastatin did not enhance the expression of tristetraprolin.


CONCLUSIONS
Simvastatin inhibits the production of TNF-alpha and IL-6 from activated mast cells in part by inhibiting de novo synthesis of their transcripts and the inhibition may account for the anti-inflammatory effect of simvastatin.
Kagami
Shin-ichiro
S
Department of Molecular Genetics, Graduate School of Medicine, Chiba University, Chiba, Japan.
Kanari
Hiroko
H
Suto
Akira
A
Fujiwara
Michio
M
Ikeda
Kei
K
Hirose
Koichi
K
Watanabe
Norihiko
N
Iwamoto
Itsuo
I
Nakajima
Hiroshi
H
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D019821:Simvastatin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019821:Simvastatin