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.
CONCLUSION: 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.