title: Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, function as inhibitors of cellular and molecular components involved in type I interferon production.
abstract: OBJECTIVE
  Statins, which are used as cholesterol-lowering agents, have pleiotropic immunomodulatory properties. Although beneficial effects of statins have been reported in autoimmune diseases, the mechanisms of these immunomodulatory effects are still poorly understood. Type I interferons (IFNs) and plasmacytoid dendritic cells (PDCs) represent key molecular and cellular pathogenic components in autoimmune diseases such as systemic lupus erythematosus (SLE). Therefore, PDCs may be a specific target of statins in therapeutic strategies against SLE. This study was undertaken to investigate the immunomodulatory mechanisms of statins that target the IFN response in PDCs.
  
  
  METHODS
  We isolated human blood PDCs by flow cytometry and examined the effects of simvastatin and pitavastatin on PDC activation, IFNalpha production, and intracellular signaling.
  
  
  RESULTS
  Statins inhibited IFNalpha production profoundly and tumor necrosis factor alpha production modestly in human PDCs in response to Toll-like receptor ligands. The inhibitory effect on IFNalpha production was reversed by geranylgeranyl pyrophosphate and was mimicked by either geranylgeranyl transferase inhibitor or Rho kinase inhibitor, suggesting that statins exert their inhibitory actions through geranylgeranylated Rho inactivation. Statins inhibited the expression of phosphorylated p38 MAPK and Akt, and the inhibitory effect on the IFN response was through the prevention of nuclear translocation of IFN regulatory factor 7. In addition, statins had an inhibitory effect on both IFNalpha production by PDCs from SLE patients and SLE serum-induced IFNalpha production.
  
  
  CONCLUSIONS
  Our findings suggest a specific role of statins in controlling type I IFN production and a therapeutic potential in IFN-related autoimmune diseases such as SLE.
authors.affiliation: Kansai Medical University, Moriguchi, Osaka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Amuro
authors.forename: Tomoki
authors.initials: T
authors.lastname: Ito
authors.forename: Rie
authors.initials: R
authors.lastname: Miyamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Yoshitaro
authors.initials: Y
authors.lastname: Torii
authors.forename: Yonsu
authors.initials: Y
authors.lastname: Son
authors.forename: Naoto
authors.initials: N
authors.lastname: Nakamichi
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yamazaki
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Hoshino
authors.forename: Tsuneyasu
authors.initials: T
authors.lastname: Kaisho
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ozaki
authors.forename: Muneo
authors.initials: M
authors.lastname: Inaba
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Amakawa
authors.forename: Shirou
authors.initials: S
authors.lastname: Fukuhara
mesh_terms: D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007370:Interferon Type I / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007370:Interferon Type I