Inhibition of anthrax lethal toxin-induced cytolysis of RAW264.7 cells by celastrol.
Inhibition of anthrax lethal toxin-induced cytolysis of RAW264.7 cells by celastrol.
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DOI：
10.1371/journal.pone.0001421
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发表时间：
2008-01-09
期刊：
影响因子：
3.7
通讯作者：
Mogridge J
中科院分区：
文献类型：
--
作者：
Chapelsky S;Batty S;Frost M;Mogridge J
炭疽杆菌是导致炭疽病的细菌。B的能力。炭疽菌致病的关键在于一种分泌的毒力因子，即致命毒素，它通过削弱免疫反应来促进细菌在宿主体内的存活。致死毒素的一个充分研究的作用是杀死巨噬细胞，尽管所涉及的分子机制尚未完全表征。在这里，我们证明，雷公藤红素，醌甲基化三萜来自植物提取物中使用的草药，抑制致死毒素诱导的死亡RAW 264.7小鼠巨噬细胞。雷公藤红素不能阻止有丝分裂原活化蛋白激酶激酶1（毒素的胞质靶点）的裂解，表明它不能抑制致死毒素的摄取或催化活性。令人惊讶的是，雷公藤红素在中毒后1.5小时内添加时几乎提供了完全的保护，表明它可以在中毒的后期阶段拯救细胞。由于蛋白酶体的活性与使用其他药物的中毒有关，我们测试了雷公藤红素是否阻断蛋白酶体活性。我们发现雷公藤红素抑制蛋白酶体依赖性的蛋白质降解RAW264.7细胞，但只有轻微抑制蛋白酶体介导的切割荧光底物在体外。此外，雷公藤红素阻断IL-18加工的刺激，表明雷公藤红素在炎性小体活化的上游起作用。这项工作确定雷公藤红素作为致死毒素介导的巨噬细胞溶解的抑制剂，并提出了一种抑制机制，涉及抑制蛋白酶体途径。
Bacillus anthracis is the bacterium responsible for causing anthrax. The ability of B. anthracis to cause disease is dependent on a secreted virulence factor, lethal toxin, that promotes survival of the bacteria in the host by impairing the immune response. A well-studied effect of lethal toxin is the killing of macrophages, although the molecular mechanisms involved have not been fully characterized. Here, we demonstrate that celastrol, a quinone methide triterpene derived from a plant extract used in herbal medicine, inhibits lethal toxin-induced death of RAW264.7 murine macrophages. Celastrol did not prevent cleavage of mitogen activated protein kinase kinase 1, a cytosolic target of the toxin, indicating that it did not inhibit the uptake or catalytic activity of lethal toxin. Surprisingly, celastrol conferred almost complete protection when it was added up to 1.5 h after intoxication, indicating that it could rescue cells in the late stages of intoxication. Since the activity of the proteasome has been implicated in intoxication using other pharmacological agents, we tested whether celastrol blocked proteasome activity. We found that celastrol inhibited the proteasome-dependent degradation of proteins in RAW264.7 cells, but only slightly inhibited proteasome-mediated cleavage of fluorogenic substrates in vitro. Furthermore, celastrol blocked stimulation of IL-18 processing, indicating that celastrol acted upstream of inflammasome activation. This work identifies celastrol as an inhibitor of lethal toxin-mediated macrophage lysis and suggests an inhibitory mechanism involving inhibition of the proteasome pathway.
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炭疽致死的毒素介导的人和鼠树突状细胞杀死损害适应性免疫反应。
影响因子：
6.7
作者：
Alileche, Abdelkrim;Serfass, Evan R;Muehlbauer, Stefan M;Porcelli, Steven A;Brojatsch, Jurgen
通讯作者：
Brojatsch, Jurgen
影响因子：
4.4
作者：
Crawford, Matthew A.;Aylott, Caroline V.;Bokoch, Gary M.
通讯作者：
Bokoch, Gary M.
影响因子：
4.3
作者：
Alileche, A;Squires, RC;Brojatsch, J
通讯作者：
Brojatsch, J
DOI：
10.1083/jcb.200211018
发表时间：
2003-02-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Abrami L;Liu S;Cosson P;Leppla SH;van der Goot FG
通讯作者：
van der Goot FG
影响因子：
3.6
作者：
Guidi-Rontani, C;Weber-Levy, M;Mock, M
通讯作者：
Mock, M