Mechanisms involved in apoptosis of human macrophages induced by lipopolysaccharide from Actinobacillus actinomycetemcomitans in the presence of cycloheximide
Mechanisms involved in apoptosis of human macrophages induced by lipopolysaccharide from Actinobacillus actinomycetemcomitans in the presence of cycloheximide
复制标题
DOI：
10.1128/iai.72.4.1856-1865.2004
复制
发表时间：
2004-04-01
影响因子：
3.1
通讯作者：
Hasegawa, K
中科院分区：
文献类型：
--
作者：
Suzuki, T;Kobayashi, M;Hasegawa, K
伴放线放线杆菌是一种主要的牙周致病菌，具有多种毒力因子，包括脂多糖（LPS）。先前的报道已经证明，LPS诱导小鼠巨噬细胞样细胞系J744.1以及C3 H/HeN小鼠腹腔巨噬细胞在放线菌酮（CHX）存在下的凋亡。然而，LPS和CHX诱导巨噬细胞凋亡的分子机制尚不清楚。为了阐明LPS在诱导巨噬细胞凋亡中的可能作用，我们研究了A.用12-O-十四烷酰佛波醇13-乙酸酯（TPA）诱导人巨噬细胞样U937细胞分化，并对该过程中的分子机制进行了评估。我们发现TPA分化的U937细胞通常表现出对LPS诱导的凋亡的抵抗。然而，在CHX的存在下，LPS诱导细胞色素c的释放而不改变Bcl-2、Bcl-xL、Bax和巴克的稳态水平。在CHX存在下用LPS处理也导致半胱天冬酶-3活化和部分经由CD 14/toll样受体4（TLR 4）的细胞凋亡。细胞色素c释放的诱导可能是由于Akt和Bad的去磷酸化，这是由CHX和LPS协同诱导的。然而，内源性肿瘤坏死因子α和Fas诱导的信号，细胞外信号调节激酶激酶/丝裂原活化蛋白激酶和I-kappaB α/核因子-kappaB（NF-κ B）是不需要caspase-3依赖性凋亡。这些结果强调了在CHX存在下，导致caspase-3活化的线粒体凋亡途径在LPS诱导的人巨噬细胞凋亡中可能的重要作用。
Actinobacillus actinomycetemcomitans is a major periodontopathic bacterium with multiple virulence factors, including lipopolysaccharide (LPS). Previous reports have demonstrated that LPS induced apoptosis in a murine macrophage-like cell line, J744.1, as well as in peritoneal macrophages from C3H/HeN mice in the presence of cycloheximide (CHX). However, the detailed molecular mechanisms involved in the apoptosis of macrophages induced by LPS and CHX are not well known. To clarify the possible role of LPS in the induction of macrophage apoptosis, we investigated cell death induced by LPS from A. actinomycetemcomitans and CHX in human macrophage-like U937 cells, which were differentiated by 12-O-tetradecanoylphorbol 13-acetate (TPA), and also assessed the molecular mechanisms involved in the process. We found that TPA-differentiated U937 cells usually showed resistance to LPS-induced apoptosis. However, in the presence of CHX, LPS induced release of cytochrome c without modifying steady-state levels of Bcl-2, Bcl-xL, Bax, and Bak. Treatment with LPS in the presence of CHX also led to activation of caspase-3 and apoptosis via, in part, the CD14/toll-like receptor 4 (TLR4). The induction of cytochrome c release may have been due to dephosphorylation of Akt and Bad, which were cooperatively induced by CHX and LPS. However, endogenous tumor necrosis factor alpha- and Fas-induced signals, extracellular signal-regulated kinase kinase/mitogen-activated protein kinases and I-kappaBalpha/nuclear factor-kappaB (NF-kappaB) were not required for caspase-3 -dependent apoptosis. These results emphasize the possible important role of the mitochondrial apoptotic pathway leading to caspase-3 activation in LPS-induced apoptosis of human macrophages in the presence of CHX.