Simvastatin inhibits IFN-γ-induced CD40 gene expression by suppressing STAT-1α
Simvastatin inhibits IFN-γ-induced CD40 gene expression by suppressing STAT-1α
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DOI：
10.1189/jlb.1206739
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发表时间：
2007-08-01
影响因子：
5.5
通讯作者：
Benveniste, Etty N.
中科院分区：
文献类型：
--
作者：
Lee, Sun Jung;Qin, Hongwei;Benveniste, Etty N.
CD 40是TNF受体超家族的成员，对产生性免疫应答至关重要。巨噬细胞以低水平组成性表达CD 40，其被IFN-γ增强。IFN-γ诱导的CD 40表达涉及STAT-1 α的活化以及通过对IFN-γ诱导的TNF-α产生的自分泌应答的NF-κ B活化。他汀类药物是3-羟基-3-甲基戊二酰（HMG）-CoA还原酶抑制剂，其抗炎作用与其降胆固醇作用无关。在此，我们描述了辛伐他汀（SS）通过抑制STAT-1 α表达来抑制IFN-γ诱导的CD 40表达。这导致IFN-γ处理后STAT-1 α募集到CD 40启动子的减少，以及RNA聚合酶II募集减少和H3和H4组蛋白乙酰化水平降低。SS介导的STAT-1 α抑制通过抑制组成型STAT-1 α mRNA和蛋白质表达发生。SS对CD 40和STAT-1 α的抑制作用依赖于HMG-CoA还原酶活性，因为加入甲羟戊酸可逆转抑制作用。此外，CD 40和/或STAT-1 α表达被GGTI-298或艰难梭菌毒素A（Rho家族蛋白质异戊二烯化的特异性抑制剂）抑制，表明小GTP结合蛋白参与了该过程。总的来说，这些数据表明SS通过抑制STAT 1 α和改变CD 40启动子处的转录事件来抑制IFN-γ诱导的CD 40表达。
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. 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 STAT1 alpha, and altering transcriptional events at the CD40 promoter.