Hu Xiaoyu, Li Wai-Ping, Meng Charis, Ivashkiv Lionel B
Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
J Immunol. 2003 May 1;170(9):4833-9. doi: 10.4049/jimmunol.170.9.4833.
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.
最近的报告表明，糖皮质激素（GC）免疫抑制作用的一种新机制是抑制白细胞介素-2（IL-2）和白细胞介素-12的信号传导，这两种细胞因子使用Janus激酶-信号转导子和转录激活子（JAK-STAT）信号通路。我们研究了GC是否也能阻断由γ-干扰素（IFN-γ）（一种强效促炎细胞因子）介导的JAK-STAT信号通路的激活。将地塞米松添加到外周血单核细胞（PBMC）培养物中，可显著抑制IFN-γ对信号转导子和转录激活子1（STAT1）的激活。需要数天暴露于GC才能明显抑制IFN-γ信号传导，其潜在机制是STAT1表达的下调。GC抑制了STAT1信使核糖核酸（mRNA）的表达，但不影响STAT1蛋白的稳定性。STAT1表达和IFN-γ信号传导在巨噬细胞中被优先抑制。GC并不直接作用于巨噬细胞，而是通过调节控制STAT1表达的巨噬细胞-淋巴细胞相互作用间接发挥作用。GC抑制了IFN-γ诱导的基因表达，从而证明了抑制信号转导的生理学意义。我们的研究结果确定了IFN-γ信号传导的一种新的调控水平，即GC通过调节STAT1表达来控制IFN-γ信号传导的幅度。这些结果表明，抑制IFN-γ信号传导有助于GC的免疫抑制作用。
