Simvastatin inhibits IFN--induced CD40 gene expression by suppressing STAT-1

Abstract: CD40, a member of the TNF receptor superfamily, is critical for productive immune re-sponses. Macrophages constitutively express CD40 at low levels, which are enhanced by IFN-, and IFN--induced CD40 expression involves activa-tion of STAT-1 as well as NF-B activation through an autocrine response to IFN--induced TNF- production. Statins are 3-hydroxy-3-meth-ylglutaryl (HMG)-CoA reductase inhibitors, which exert anti-inflammatory effects, independent of their cholesterol-lowering actions. Herein, we de-scribe that simvastatin (SS) inhibits IFN--induced CD40 expression via the suppression of STAT-1 expression. This results in diminished STAT-1 recruitment to the CD40 promoter upon IFN- treatment, in addition to reduced RNA Polymerase II recruitment and diminished levels of H3 and H4 histone acetylation. SS-mediated inhibition of STAT-1 occurs through suppression of constitu-tive STAT-1 mRNA and protein expression. The inhibitory effect of SS on CD40 and STAT-1 is dependent on HMG-CoA reductase activity, as the addition of mevalonate reverses the inhibitory ef-fect. In addition, CD40 and/or STAT-1 expres-sion is inhibited by GGTI-298 or Clostridium diffi-cile Toxin A, a specific inhibitor of Rho family protein prenylation, indicating the involvement of small, GTP-binding proteins in this process. Col-lectively, these data indicate that SS inhibits IFN--induced CD40 expression by suppression of STAT-1 and altering transcriptional events at th