Mycobacterium tuberculosis inhibits IFN-gamma transcriptional responses without inhibiting activation of STAT1.
Mycobacterium tuberculosis inhibits IFN-gamma transcriptional responses without inhibiting activation of STAT1.
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DOI：
10.4049/jimmunol.163.7.3898
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发表时间：
1999-10
影响因子：
4.4
通讯作者：
Li Min Ting;Anne C. Kim;Ashok Cattamanchi;Joel D. Ernst
中科院分区：
文献类型：
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作者：
Li Min Ting;Anne C. Kim;Ashok Cattamanchi;Joel D. Ernst
干扰素-γ能激活巨噬细胞杀死多种细胞内病原体，但不能激活人巨噬细胞杀死毒力强的结核分枝杆菌。我们验证了这是由于结核分枝杆菌抑制了干扰素-γ信号的假设，发现结核分枝杆菌感染人巨噬细胞可以阻断对干扰素-γ的几种反应，包括杀死弓形虫和诱导FcGammaRI。结核分枝杆菌的抑制作用是针对干扰素-γ反应基因的转录，但不影响Janus激酶-STAT途径的近端步骤，因为在结核分枝杆菌感染的细胞中，STAT1α酪氨酸和丝氨酸的磷酸化、二聚化、核转位和DNA结合是完整的。相反，在结核分枝杆菌感染的巨噬细胞中，干扰素-γ诱导的STAT1与转录共激活因子CREB结合蛋白和p300的结合显著减少，这表明结核分枝杆菌直接或间接破坏了这种蛋白质-蛋白质相互作用，这种相互作用是对干扰素-γ的转录反应至关重要的。经γ射线照射的结核分枝杆菌和分离的细胞壁复制了活细菌的作用，表明启动抑制干扰素-γ反应的细菌成分(S)是结构性表达的。虽然已发现脂阿拉伯甘露聚糖对巨噬细胞有作用，但它不能解释细胞壁的抑制作用。这些结果表明，结核分枝杆菌逃避人类免疫反应的一种机制是抑制干扰素-γ信号通路，这种抑制机制与已报道的杜氏利什曼原虫或巨细胞病毒的机制不同，因为它以STAT1与基本转录装置的相互作用为靶点。
IFN-gamma activates macrophages to kill diverse intracellular pathogens, but does not activate human macrophages to kill virulent Mycobacterium tuberculosis. We tested the hypothesis that this is due to inhibition of IFN-gamma signaling by M. tuberculosis and found that M. tuberculosis infection of human macrophages blocks several responses to IFN-gamma, including killing of Toxoplasma gondii and induction of FcgammaRI. The inhibitory effect of M. tuberculosis is directed at transcription of IFN-gamma-responsive genes, but does not affect proximal steps in the Janus kinase-STAT pathway, as STAT1alpha tyrosine and serine phosphorylation, dimerization, nuclear translocation, and DNA binding are intact in M. tuberculosis-infected cells. In contrast, there is a marked decrease in IFN-gamma-induced association of STAT1 with the transcriptional coactivators CREB binding protein and p300 in M. tuberculosis-infected macrophages, indicating that M. tuberculosis directly or indirectly disrupts this protein-protein interaction that is essential for transcriptional responses to IFN-gamma. Gamma-irradiated M. tuberculosis and isolated cell walls reproduce the effects of live bacteria, indicating that the bacterial component(s) that initiates inhibition of IFN-gamma responses is constitutively expressed. Although lipoarabinomannan has been found to exert effects on macrophages, it does not account for the inhibitory effects of cell walls. These results indicate that one mechanism for M. tuberculosis to evade the human immune response is to inhibit the IFN-gamma signaling pathway, and that the mechanism of inhibition is distinct from that reported for Leishmania donovani or CMV, in that it targets the interaction of STAT1 with the basal transcriptional apparatus.