Inhibition of IFN-γ signaling by glucocorticoids
Inhibition of IFN-γ signaling by glucocorticoids
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DOI：
10.4049/jimmunol.170.9.4833
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发表时间：
2003-05-01
影响因子：
4.4
通讯作者：
Ivashkiv, LB
中科院分区：
文献类型：
--
作者：
Hu, XY;Li, WP;Ivashkiv, LB
最近的报道表明，糖皮质激素（GC）免疫抑制作用的新机制是抑制使用Janus激酶- stat信号通路的细胞因子IL-2和IL-12的信号传导。我们研究了GCs是否也可以阻断ifn - γ（一种有效的促炎细胞因子）激活Janus激酶- stat信号。在PBMC培养中加入地塞米松可显著抑制STAT1的ifn - γ激活。暴露于GCs数天后，ifn - γ信号的抑制作用才变得明显，其潜在机制是下调STAT1的表达。GCs抑制STAT1 mRNA的表达，但不影响STAT1蛋白的稳定性。巨噬细胞中STAT1表达和ifn - γ信号优先被抑制。GCs不直接作用于巨噬细胞，而是通过调节巨噬细胞-淋巴细胞相互作用来间接作用，从而控制STAT1的表达。GCs抑制ifn - γ诱导基因的表达，从而显示了抑制信号转导的生理意义。我们的研究结果确定了ifn - γ信号的一个新的调控水平，即GCs通过调节STAT1的表达来控制ifn - γ信号的幅度。这些结果表明，抑制ifn - γ信号有助于GCs的免疫抑制作用。
Recent reports suggest that a novel mechanism of glucocorticoid (GC) immunosuppressive action is inhibition of signaling by IL-2 and IL-12, cytokines that use the Janus kinase-STAT signaling pathway. We investigated whether GCs could also block activation of Janus kinase-STAT signaling by IFN-gamma, a potent proinflammatory cytokine. Addition of dexamethasone to PBMC cultures resulted in a dramatic inhibition of IFN-gamma activation of STAT1. Several days of exposure to GCs were required for inhibition of IFN-gamma signaling to become apparent, and the underlying mechanism was down-regulation of STAT1 expression. GCs suppressed the expression of STAT1 mRNA, but did not affect STAT1 protein stability. STAT1 expression and IFN-gamma signaling were preferentially suppressed in macrophages. GCs did not act directly on macrophages, but worked indirectly by regulating macrophage-lymphocyte interactions that control STAT1 expression. GCs inhibited IFN-gamma-inducible gene expression, thus demonstrating the physiological significance of inhibition of signal transduction. Our results identify a novel level of regulation of IFN-gamma signaling, whereby GCs control the amplitude of IFN-gamma signaling by regulating STAT1 expression. These results suggest that inhibition of IFN-gamma signaling contributes to the immunosuppressive action of GCs.