Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin.
Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin.
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发表时间：
2003-03
期刊：
影响因子：
11.2
通讯作者：
T. Cover;U. Krishna;D. Israel;R. Peek
中科院分区：
文献类型：
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作者：
T. Cover;U. Krishna;D. Israel;R. Peek
幽门螺杆菌感染引起的慢性胃炎是远端胃腺癌发生的重要危险因素。宿主对H. pylori感染可能导致胃癌发生的原因是上皮细胞凋亡。本研究的目的是探讨H. pylori vacuolating toxin（VacA）诱导胃上皮细胞凋亡。与AGS胃上皮细胞共培养，H.表达s1/m1型VacA毒素的pylori菌株60190比同基因VacA无效突变菌株诱导显著更高水平的细胞凋亡。从菌株60190中纯化的VacA以剂量依赖性方式诱导细胞凋亡，这需要纯化的毒素的酸活化和氯化铵的存在。相反，在与嵌合s2/m1毒素（其中来自菌株60190的VacA NH（2）末端的s1序列被来自非致突变菌株Tx 30 a的s2序列取代）或VacA突变蛋白（VacA Delta 6-27）（在VacA NH（2）末端附近缺乏独特的强疏水区）孵育后，未诱导细胞凋亡。此外，当纯化的VacA Delta 6-27和纯化的野生型VacA的等摩尔混合物同时加入到AGS细胞中时，突变毒素表现出显性负效应，完全抑制野生型VacA的凋亡诱导活性。这些结果表明，VacA诱导胃上皮细胞凋亡，并建议在H。幽门螺杆菌感染的人可能是由于VacA结构的菌株依赖性变异。
Chronic gastritis induced by Helicobacter pylori is a strong risk factor for the development of distal gastric adenocarcinoma. A specific host response to H. pylori that may contribute to gastric carcinogenesis is epithelial cell apoptosis. The aim of this study was to investigate the capacity of H. pylori vacuolating toxin (VacA) to induce gastric epithelial cell apoptosis. When cocultured with AGS gastric epithelial cells, H. pylori strain 60190, which expresses a type s1/m1 VacA toxin, induced significantly higher levels of apoptosis than did an isogenic vacA null mutant strain. VacA purified from strain 60190 induced apoptosis in a dose-dependent manner, which required acid activation of the purified toxin and the presence of ammonium chloride. In contrast, apoptosis was not induced after incubation with a chimeric s2/m1 toxin (in which the s1 sequence at the NH(2) terminus of VacA from strain 60190 was replaced with the s2 sequence from the nontoxigenic strain Tx30a) or a VacA mutant protein (VacA Delta 6-27) that lacks a unique strongly hydrophobic region near the VacA NH(2) terminus. Moreover, when an equimolar mixture of purified VacA Delta 6-27 and purified wild-type VacA were added simultaneously to AGS cells, the mutant toxin exhibited a dominant negative effect, completely inhibiting the apoptosis-inducing activity of wild-type VacA. These results indicate that VacA induces gastric epithelial cell apoptosis and suggest that differences in levels of gastric mucosal epithelial apoptosis among H. pylori-infected persons may result from strain-dependent variations in VacA structure.