Zhou Yang, Zhao Deming, Yue Ruichao, Khan Sher Hayat, Shah Syed Zahid Ali, Yin Xiaomin, Yang Lifeng, Zhang Zhongqiu, Zhou Xiangmei
State Key Laboratories for Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China.
Antonie Van Leeuwenhoek. 2015 Jul;108(1):163-71. doi: 10.1007/s10482-015-0475-6. Epub 2015 May 16.
Mycobacterium bovis is the causative agent of tuberculosis in cattle. Infection of macrophages with M. bovis leads to the activation of the "nucleotide binding and oligomerization, leucine-rich repeat and pyrin domains-containing protein 3" (NLRP3) and "absent in melanoma 2" (AIM2) inflammasomes, which in turn triggers release of the proinflammatory cytokine interleukin-1β (IL-1β) that contributes to bacterial clearance and plays a crucial role in the host defense. However, NLRP3 and AIM2 inflammasome activation is influenced by several factors and how IL-1β secretion by M. bovis-infected macrophages is regulated via the inflammasome pathway remains unclear. Here we found that IL-1β secretion and pro-IL-1β protein accumulation were inhibited in THP-1 macrophages upon exposure to the virulent M. bovis Beijing strain in the presence of high K(+) concentrations, cycloheximide (a protein synthesis inhibitor) and PR-619 (a deubiquitinating enzyme inhibitor). Scavenging reactive oxygen species (ROS) induced by N-acetylcysteine reduced IL-1β release independent of the mitochondrial permeability transition. Collectively, our results suggest that IL-1β secretion by M. bovis-infected THP-1 macrophages is reduced by high extracellular K(+) concentration, inhibition of new protein synthesis, deubiquitination, and ROS generation.
牛分枝杆菌是牛结核病的病原体。牛分枝杆菌感染巨噬细胞会导致“含核苷酸结合和寡聚化、富含亮氨酸重复序列和pyrin结构域的蛋白3”（NLRP3）和“黑色素瘤2缺失蛋白”（AIM2）炎性小体的激活，进而触发促炎细胞因子白细胞介素-1β（IL-1β）的释放，这有助于细菌清除并在宿主防御中发挥关键作用。然而，NLRP3和AIM2炎性小体的激活受多种因素影响，牛分枝杆菌感染的巨噬细胞通过炎性小体途径分泌IL-1β的调控方式仍不清楚。在此，我们发现，在高钾浓度、放线菌酮（一种蛋白质合成抑制剂）和PR-619（一种去泛素化酶抑制剂）存在的情况下，THP-1巨噬细胞暴露于强毒牛分枝杆菌北京株后，IL-1β的分泌和前体IL-1β蛋白的积累受到抑制。用N-乙酰半胱氨酸清除活性氧（ROS）可降低IL-1β的释放，且与线粒体通透性转换无关。总的来说，我们的结果表明，高细胞外钾浓度、新蛋白质合成的抑制、去泛素化和ROS生成会降低牛分枝杆菌感染的THP-1巨噬细胞中IL-1β的分泌。
