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Published online before print May 16, 2007

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(Journal of Leukocyte Biology. 2007;82:436-447.)
© 2007 by Society for Leukocyte Biology

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

Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA

¹ Correspondence: Department of Cell Biology, 1918 University Blvd., MCLM 395A, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA. E-mail: tika{at}uab.edu

CD40, a member of the TNF receptor superfamily, is critical for productive immune responses. Macrophages constitutively express CD40 at low levels, which are enhanced by IFN-. IFN--induced CD40 expression involves activation of STAT-1 as well as NF-B activation through an autocrine response to IFN--induced TNF- production. Statins are 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, which exert anti-inflammatory effects independent of their cholesterol-lowering actions. Herein, we describe 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 constitutive 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 effect. In addition, CD40 and/or STAT-1 expression is inhibited by GGTI-298 or Clostridium difficile Toxin A, a specific inhibitor of Rho family protein prenylation, indicating the involvement of small GTP-binding proteins in this process. Collectively, these data indicate that SS inhibits IFN--induced CD40 expression by suppression of STAT-1, and altering transcriptional events at the CD40 promoter.

Key Words: statins • JAK-STAT pathway • macrophage