Highly homologous Mycobacterium tuberculosis chaperonin 60 proteins with differential CD14 dependencies stimulate cytokine production by human monocytes through cooperative activation of p38 and ERK1/2 mitogen-activated protein kinases
Highly homologous Mycobacterium tuberculosis chaperonin 60 proteins with differential CD14 dependencies stimulate cytokine production by human monocytes through cooperative activation of p38 and ERK1/2 mitogen-activated protein kinases
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DOI：
10.1016/j.intimp.2006.10.005
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发表时间：
2007-02-01
影响因子：
5.6
通讯作者：
Henderson, Brian
中科院分区：
文献类型：
--
作者：
Lewthwaite, Jo C.;Clarkin, Claire E.;Henderson, Brian
结核病是由结核分枝杆菌感染引起的一种慢性炎症性和破坏性疾病。我们之前已经证明分枝杆菌伴侣蛋白（Cpn）60.1和60.2蛋白刺激人类单核细胞分泌促炎细胞因子。因此，确定以肌杆菌感染为特征的慢性炎症的细胞机制具有潜在的治疗益处。在本研究中，我们研究了细胞外信号调节（ERK1/2）和p38丝裂原活化蛋白激酶（MAPK）家族在cpn60诱导的细胞因子合成中的作用，并比较了细菌蛋白与脂多糖（LPS）的作用。暴露于Cpn60.1、Cpn60.2或LPS可增强ERK1/2的激活，磷酸化在刺激后10 - 30分钟明显增加，在刺激后60-90分钟达到最大。在cpn60刺激的单核细胞中，ERK1/2的磷酸化保持不变，而在lps刺激的细胞中，ERKI/2迅速去磷酸化。暴露于伴侣蛋白也引起p38（mapk）的快速激活，其磷酸化动力学与LPS反应中观察到的相似。p38(mapk) （SB203580）或MEK1/2 （ERK1/2的直接上游激活因子）（PD98059）的选择性抑制剂可减少伴侣蛋白或LPS诱导的IL-1 β、TNF α、IL-6和IL-8的合成。实验中，细胞暴露于这两种抑制剂的组合导致几乎完全废除激动剂诱导的细胞因子合成。这些结果表明，P38（mapk）和ERK1/2信号通路是分枝杆菌伴侣蛋白的细胞反应的重要调节因子，并且这些通路协同调节人单核细胞的促炎细胞因子产生。(c) 2006 Elsevier B.V.版权所有
Tuberculosis is a chronic inflammatory and destructive disease caused by infection with Mycobacterium tuberculosis. We have previously shown that the mycobacterial chaperonin (Cpn)60.1 and 60.2 proteins stimulate human monocytes to secrete pro-inflammatory cytokines.Identification of the cellular mechanisms that contribute to the chronic inflammation characterised by myobacterial infection is therefore of potential therapeutic benefit. In the present study we have investigated the role of the extracellular signal-regulated (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) families in Cpn60-induced cytokine synthesis, and have compared the effects of the bacterial proteins with those of lipopolysaccharide (LPS). Exposure to Cpn60.1, Cpn60.2 or LPS enhanced ERK1/2 activation with increases in phosphorylation evident between 10 and 30 min and maximal after 60-90 min stimulation. Phosphorylation of ERK1/2 in Cpn60-stimulated monocytes was maintained whereas ERKI/2 was rapidly dephosphorylated in LPS-stimulated cells. Exposure to the chaperonins also caused rapid activation of p38(mapk) with kinetics of phosphorylation comparable to those observed in response to LPS. Selective inhibitors of p38(mapk) (SB203580) or of MEK1/2, the direct upstream activator of ERK1/2 (PD98059), reduced the synthesis of IL-1 beta TNF alpha, IL-6 and IL-8 induced by either the chaperonins or LPS. Experiments in which cells were exposed to a combination of both inhibitors led to a nearly complete abrogation of agonist-induced cytokine synthesis. These results show that the P38(mapk) and ERK1/2 signalling pathways are important regulators of the cellular response to mycobacterial chaperonins and that these pathways cooperate to regulate pro-inflammatory cytokine production by human monocytes. (c) 2006 Elsevier B.V. All rights reserved.