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Simvastatin inhibits IFN‐γ‐induced CD40 gene expression by suppressing STAT‐1α
Author(s) -
Lee Sun Jung,
Qin Hongwei,
Benveniste Etty N.
Publication year - 2007
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.1206739
Subject(s) - biology , stat , cd40 , simvastatin , microbiology and biotechnology , socs3 , hmg coa reductase , cancer research , signal transduction , reductase , stat3 , biochemistry , pharmacology , cytotoxic t cell , enzyme , in vitro
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‐γ. IFN‐γ‐induced CD40 expression involves activation of STAT‐1α as well as NF‐κB activation through an autocrine response to IFN‐γ‐induced TNF‐α 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‐γ‐induced CD40 expression via the suppression of STAT‐1α expression. This results in diminished STAT‐1α recruitment to the CD40 promoter upon IFN‐γ treatment, in addition to reduced RNA Polymerase II recruitment and diminished levels of H3 and H4 histone acetylation. SS‐mediated inhibition of STAT‐1α occurs through suppression of constitutive STAT‐1α mRNA and protein expression. The inhibitory effect of SS on CD40 and STAT‐1α is dependent on HMG‐CoA reductase activity, as the addition of mevalonate reverses the inhibitory effect. In addition, CD40 and/or STAT‐1α 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‐γ‐induced CD40 expression by suppression of STAT‐1α, and altering transcriptional events at the CD40 promoter.