title: HMG-CoA reductase inhibitor simvastatin inhibits proinflammatory cytokine production from murine mast cells.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Kagami
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kanari
authors.forename: Akira
authors.initials: A
authors.lastname: Suto
authors.forename: Michio
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Kei
authors.initials: K
authors.lastname: Ikeda
authors.forename: Koichi
authors.initials: K
authors.lastname: Hirose
authors.forename: Norihiko
authors.initials: N
authors.lastname: Watanabe
authors.forename: Itsuo
authors.initials: I
authors.lastname: Iwamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakajima
mesh_terms: 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
chemical_list: D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019821:Simvastatin