Innate inhibition of adaptive immunity:: Mycobacterium tuberculosis-induced IL-6 inhibits macrophage responses to IFN-γ
Innate inhibition of adaptive immunity:: Mycobacterium tuberculosis-induced IL-6 inhibits macrophage responses to IFN-γ
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DOI：
10.4049/jimmunol.171.9.4750
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发表时间：
2003-11-01
影响因子：
4.4
通讯作者：
Ernst, JD
中科院分区：
文献类型：
--
作者：
Nagabhushanam, V;Solache, A;Ernst, JD
在人类和小鼠中，控制胞内病原体结核分枝杆菌（Mtb）需要IFN-γ。尽管适应性免疫应答导致响应于Mtb产生大量IFN-γ，但在大多数情况下免疫应答不能根除感染。我们先前已经报道了Mtb抑制巨噬细胞对IFN-γ的应答的证据，这表明这可能限制IFN-γ刺激巨噬细胞杀死Mtb的能力。我们还观察到，培养物中与感染的巨噬细胞相邻的未感染的巨噬细胞对IFN-γ的反应减弱。在这里，我们报告说，结核分枝杆菌感染的巨噬细胞分泌的IL-6抑制未感染的巨噬细胞对IFN-γ的反应。IL-6在转录激活水平上选择性地抑制IFN-γ应答基因的子集，而不抑制STAT 1的激活或功能。通过IL-6抑制巨噬细胞对IFN-γ的反应需要新的蛋白质合成，但这种作用不能归因于细胞因子信号转导抑制因子1或3。这些结果揭示了IL-6的新功能，并表明Mtb感染的巨噬细胞分泌的IL-6可能导致细胞免疫应答无法根除感染。
In humans and in mice, control of the intracellular pathogen, Mycobacterium tuberculosis (Mtb), requires IFN-gamma. Although the adaptive immune response results in production of substantial amounts of IFN-gamma in response to Mtb, the immune response is unable to eradicate the infection in most cases. We have previously reported evidence that Mtb inhibits macrophage responses to IFN-gamma suggesting that this may limit the ability of IFN-gamma to stimulate macrophages to kill Mtb. We have also observed that uninfected macrophages, adjacent to infected macrophages in culture, exhibit decreased responses to IFN-gamma. Here we report that IL-6 secreted by Mtb-infected macrophages inhibits the responses of uninfected macrophages to IFN-gamma. IL-6 selectively inhibits a subset of IFN-gamma-responsive genes at the level of transcriptional activation without inhibiting activation or function of STAT1. Inhibition of macrophage responses to IFN-gamma by IL-6 requires new protein synthesis, but this effect is not attributable to suppressor of cytokine signaling 1 or 3. These results reveal a novel function for IL-6 and indicate that IL-6 secreted by Mtb-infected macrophages may contribute to the inability of the cellular immune response to eradicate infection.