Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis.
Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis.
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DOI：
10.4049/jimmunol.163.7.3920
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发表时间：
1999-10
影响因子：
4.4
通讯作者：
T. Means;Shuyan Wang;E. Lien;A. Yoshimura;D. Golenbock;M. Fenton
中科院分区：
文献类型：
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作者：
T. Means;Shuyan Wang;E. Lien;A. Yoshimura;D. Golenbock;M. Fenton
最近的研究表明，哺乳动物Toll样受体（TLR）家族参与了革兰氏阴性和革兰氏阳性细菌产物对巨噬细胞的激活。我们以前已经表明，不同的TLR蛋白介导的不同的CD14配体革兰氏阴性细菌LPS和分枝杆菌糖脂脂阿拉伯甘露聚糖（LAM）的细胞活化。在这里，我们表明，活的结核分枝杆菌激活中国仓鼠卵巢细胞和小鼠巨噬细胞过度表达TLR2或TLR4。这与革兰氏阳性菌和鸟分枝杆菌形成对比，它们通过TLR2而不是TLR4激活细胞。对M.结核病可以TLR依赖的方式激活细胞。无论是膜结合或可溶性CD14是需要杆菌激活细胞的TLR依赖性方式。我们还评估了LAM是否是负责TLR依赖性细胞激活的分枝杆菌细胞壁成分。结核我们发现TLR2，而不是TLR4，可以赋予从快速生长的分枝杆菌中分离的LAM的反应性。而从M.结核分枝杆菌或牛分枝杆菌卡介苗未能诱导TLR依赖性激活。最后，可溶性和细胞壁相关的分枝杆菌因子都能够通过不同的TLR蛋白介导激活。发现可溶性热稳定和蛋白酶抗性因子介导TLR 2依赖性激活，而热敏感细胞相关分支杆菌因子介导TLR 4依赖性激活。总之，我们的数据表明，Toll样受体可以介导M。通过与分枝杆菌细胞壁糖脂LAM不同的CD14非依赖性配体治疗结核病。
Recent studies have implicated a family of mammalian Toll-like receptors (TLR) in the activation of macrophages by Gram-negative and Gram-positive bacterial products. We have previously shown that different TLR proteins mediate cellular activation by the distinct CD14 ligands Gram-negative bacterial LPS and mycobacterial glycolipid lipoarabinomannan (LAM). Here we show that viable Mycobacterium tuberculosis bacilli activated both Chinese hamster ovary cells and murine macrophages that overexpressed either TLR2 or TLR4. This contrasted with Gram-positive bacteria and Mycobacterium avium, which activated cells via TLR2 but not TLR4. Both virulent and attenuated strains of M. tuberculosis could activate the cells in a TLR-dependent manner. Neither membrane-bound nor soluble CD14 was required for bacilli to activate cells in a TLR-dependent manner. We also assessed whether LAM was the mycobacterial cell wall component responsible for TLR-dependent cellular activation by M. tuberculosis. We found that TLR2, but not TLR4, could confer responsiveness to LAM isolated from rapidly growing mycobacteria. In contrast, LAM isolated from M. tuberculosis or Mycobacterium bovis bacillus Calmette-Guérin failed to induce TLR-dependent activation. Lastly, both soluble and cell wall-associated mycobacterial factors were capable of mediating activation via distinct TLR proteins. A soluble heat-stable and protease-resistant factor was found to mediate TLR2-dependent activation, whereas a heat-sensitive cell-associated mycobacterial factor mediated TLR4-dependent activation. Together, our data demonstrate that Toll-like receptors can mediate cellular activation by M. tuberculosis via CD14-independent ligands that are distinct from the mycobacterial cell wall glycolipid LAM.