HMG-CoA Reductase Inhibitor Simvastatin Inhibits Proinflammatory Cytokine Production from Murine Mast CellsKagami S. · Kanari H. · Suto A. · Fujiwara M. · Ikeda K. · Hirose K. · Watanabe N. · Iwamoto I. · Nakajima H.
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-α 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-α mRNA, was evaluated. Results: Incubation of BMMCs with simvastatin resulted in the inhibition of LPS-induced TNF-α 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-α 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.
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