Mycobacterium tuberculosis heat shock proteins use diverse toll-like receptor pathways to activate pro-inflammatory signals
Mycobacterium tuberculosis heat shock proteins use diverse toll-like receptor pathways to activate pro-inflammatory signals
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DOI：
10.1074/jbc.m411379200
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发表时间：
2005-06-03
影响因子：
4.8
通讯作者：
Arditi, M
中科院分区：
文献类型：
--
作者：
Bulut, Y;Michelsen, KS;Arditi, M
虽然结核分枝杆菌膜和分泌因子所使用的Toll样受体是已知的，但结核分枝杆菌膜激活的途径是已知的。结核热休克蛋白则不然。针对胞内病原体M的有效免疫应答。结核病严重依赖于先天免疫系统对入侵病原体的快速检测和适应性免疫应答的协调激活。巨噬细胞吞噬M.结核病伴随着转录因子NF-κ B B的激活和炎症介质的分泌，这些炎症介质在M.肺结核感染。M.结核病与各种Toll样受体的相互作用是复杂的，并且似乎不同的分枝杆菌组分可能与Toll样受体家族的不同成员相互作用。在这里，我们表明，重组，纯化，分枝杆菌热休克蛋白65和70诱导NF-κ B B活性在人内皮细胞中以剂量依赖性的方式。此外，我们发现，而分枝杆菌热休克蛋白65信号完全通过Toll样受体4，热休克蛋白70也通过Toll样受体2的信号。分枝杆菌热休克蛋白65诱导的NF-κ B活化是MyD 88、TIRAP、TRIF和TRAM依赖性的，并且需要MD-2的存在。更好地认识分枝杆菌热休克蛋白及其在宿主对病原体的免疫应答中的作用，可能会为更好地理解这种重要的人类病原体诱导的免疫过程和宿主-病原体相互作用开辟道路，并可能有助于更有效的疫苗或疫苗佐剂的合理设计。
Although the Toll-like receptors used by Mycobacterium tuberculosis membrane and secreted factors are known, the pathways activated by M. tuberculosis heat shock proteins are not. An efficient immune response against the intracellular pathogen M. tuberculosis is critically dependent on rapid detection of the invading pathogen by the innate immune system and coordinated activation of the adaptive immune response. Macrophage phagocytosis of M. tuberculosis is accompanied by activation of the transcription factor NF-kappa B and secretion of inflammatory mediators that play an important role in granuloma formation and immune protection during M. tuberculosis infection. The interaction between M. tuberculosis and the various Toll-like receptors is complex, and it appears that distinct mycobacterial components may interact with different members of the Toll-like receptor family. Here we show that recombinant, purified, mycobacterial heat shock proteins 65 and 70 induce NF-kappa B activity in a dose-dependent manner in human endothelial cells. Furthermore, we show that whereas mycobacterial heat shock protein 65 signals exclusively through Toll-like receptor 4, heat shock protein 70 also signals through Toll-like receptor 2. Mycobacterial heat shock protein 65-induced NF-kappa B activation was MyD88-, TIRAP-, TRIF-, and TRAM-dependent and required the presence of MD-2. A better understanding of the recognition of mycobacterial heat shock proteins and their role in the host immune response to the pathogen may open the way to a better understanding of the immunological processes induced by this important human pathogen and the host-pathogen interactions and may help in the rational design of more effective vaccines or vaccine adjuvants.