Journal of Leukocyte Biology
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A more recent version of this article appeared on August 1, 2007

Published online before print May 16, 2007
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1206739

Received for publication December 20, 2006.
Revised April 5, 2007.
Accepted for publication April 26, 2007.

Article

Simvastatin inhibits IFN-{gamma}-induced CD40 gene expression by suppressing STAT-1{alpha}

Sun Jung Lee , Hongwei Qin , and Etty N. Benveniste @

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

@ To whom correspondence should be addressed. E-mail: tika{at}uab.edu.


  Abstract

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-{gamma}, and IFN-{gamma}-induced CD40 expression involves activation of STAT-1{alpha} as well as NF-{kappa}B activation through an autocrine response to IFN-{gamma}-induced TNF-{alpha} 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-{gamma}-induced CD40 expression via the suppression of STAT-1{alpha} expression. This results in diminished STAT-1{alpha} recruitment to the CD40 promoter upon IFN-{gamma} treatment, in addition to reduced RNA Polymerase II recruitment and diminished levels of H3 and H4 histone acetylation. SS-mediated inhibition of STAT-1{alpha} occurs through suppression of constitutive STAT-1{alpha} mRNA and protein expression. The inhibitory effect of SS on CD40 and STAT-1{alpha} is dependent on HMG-CoA reductase activity, as the addition of mevalonate reverses the inhibitory effect. In addition, CD40 and/or STAT-1{alpha} 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-{gamma}-induced CD40 expression by suppression of STAT-1{alpha} and altering transcriptional events at the CD40 promoter.

Key Words: statins • JAK-STAT pathway • macrophage






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