HMG-CoA Reductase Inhibitor Simvastatin Inhibits Proinflammatory Cytokine Production from Murine Mast CellsKagami S.a, b · Kanari H.a · Suto A.a, b · Fujiwara M.b · Ikeda K.b · Hirose K.b · Watanabe N.b · Iwamoto I.c · Nakajima H.a, b
aDepartment of Molecular Genetics, Graduate School of Medicine, Chiba University, bDepartment of Allergy and Clinical Immunology, Chiba University Hospital and cResearch Center for Allergy and Clinical Immunology, Asahi General Hospital, Chiba, Japan
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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.
© 2008 S. Karger AG, Basel
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