Mycobacterium tuberculosis inhibits macrophage responses to IFN-γ through myeloid differentiation factor 88-dependent and -independent mechanisms
Mycobacterium tuberculosis inhibits macrophage responses to IFN-γ through myeloid differentiation factor 88-dependent and -independent mechanisms
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DOI：
10.4049/jimmunol.172.10.6272
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发表时间：
2004-05-15
影响因子：
4.4
通讯作者：
Ernst, JD
中科院分区：
文献类型：
--
作者：
Fortune, SM;Solache, A;Ernst, JD
结核分枝杆菌克服巨噬细胞的杀菌活性，在细胞内持续存在。结核分枝杆菌避免巨噬细胞杀伤的一种机制可能是通过抑制ifn - γ介导的信号传导。在这项研究中，我们提供的证据表明，结核分枝杆菌至少有两种不同的成分，19 kda脂蛋白和细胞壁肽聚糖（包含在真菌乳酸半乳糖肽聚糖（mAGP）复合物中），在转录水平上抑制巨噬细胞对ifn - γ的反应。此外，这些成分参与不同的近端信号通路来抑制对ifn - γ的反应：19 kda脂蛋白以toll样受体（TLR）2依赖性和髓细胞分化因子88依赖性的方式抑制ifn - γ信号，而mAGP则独立抑制TLR2、TLR4和髓细胞分化因子88。除了抑制特异性ifn - γ应答基因的诱导外，19 kda脂蛋白和mAGP抑制ifn - γ激活小鼠巨噬细胞杀死毒性结核分枝杆菌的能力，而不抑制NO的产生。这些结果表明，抑制巨噬细胞对ifn - γ的反应可能导致无法明显有效地根除结核分枝杆菌的免疫反应。
Mycobacterium tuberculosis overcomes macrophage bactericidal activities and persists intracellularly. One mechanism by which M. tuberculosis avoids macrophage killing might be through inhibition of IFN-gamma-mediated signaling. In this study we provide evidence that at least two distinct components of M. tuberculosis, the 19-kDa lipoprotein and cell wall peptidoglycan (contained in the mycolylarabinogalactan peptidoglycan (mAGP) complex), inhibit macrophage responses to IFN-gamma at a transcriptional level. Moreover, these components engage distinct proximal signaling pathways to inhibit responses to IFN-gamma: the 19-kDa lipoprotein inhibits IFN-gamma signaling in a Toll-like receptor (TLR)2-dependent and myeloid differentiation factor 88-dependent fashion whereas mAGP inhibits independently of TLR2, TLR4, and myeloid differentiation factor 88. In addition to inhibiting the induction of specific IFN-gamma responsive genes, the 19-kDa lipoprotein and mAGP inhibit the ability of IFN-gamma to activate murine macrophages to kill virulent M. tuberculosis without inhibiting production of NO. These results imply that inhibition of macrophage responses to IFN-gamma may contribute to the inability of an apparently effective immune response to eradicate M. tuberculosis.