Helicobacter pylori VacA activates the p38/activating transcription factor 2-mediated signal pathway in AZ-521 cells
Helicobacter pylori VacA activates the p38/activating transcription factor 2-mediated signal pathway in AZ-521 cells
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DOI：
10.1074/jbc.m308898200
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发表时间：
2004-02-20
影响因子：
4.8
通讯作者：
Hirayama, T
中科院分区：
文献类型：
--
作者：
Nakayama, M;Kimura, M;Hirayama, T
幽门螺杆菌在胃中的持续定植诱导胃炎和消化性溃疡，并干扰溃疡愈合。大多数H.幽门螺杆菌产生细胞毒素VacA，其诱导上皮细胞中的细胞质空泡化，伴随结构和功能变化，导致胃损伤。已知VacA通过线粒体损伤引起细胞死亡。我们假设VacA可能会破坏其他信号通路;为此，我们研究了VacA对MAPKs的影响，以阐明它们在VacA处理的细胞中观察到的异常中的作用。VacA刺激AZ-521细胞中p38和Erk 1/2的磷酸化，但不刺激JNK。加入VacA后10-30 min，p38的磷酸化和激酶活化达到最大，此后下降。用抗VacA抗体或p38抑制剂SB 203580处理阻断了由VacA引起的p38磷酸化，并抑制了VacA诱导的转录激活因子2（ATF-2）的磷酸化，ATF-2与应激反应基因的转录控制有关。这些数据表明，VacA刺激p38/ ATF-2介导的信号通路。然而，足以降低p38磷酸化的10 μ M SB 203580不能抑制VacA诱导的细胞空泡化、线粒体膜电位降低或线粒体释放细胞色素c。这些结果表明，VacA诱导的p38/ATF-2介导的信号通路的激活是独立的细胞空泡化，降低线粒体膜电位，或细胞色素c从线粒体释放的VacA引起的。因此，细胞毒素可以独立地作用于几个细胞靶点，导致信号传导、调节和代谢途径的破坏。
Persistent Helicobacter pylori colonization in the stomach induces gastritis and peptic ulcer and interferes with ulcer healing. Most strains of H. pylori produce a cytotoxin, VacA, that induces cytoplasmic vacuolation in epithelial cells with structural and functional changes, leading to gastric injury. VacA is known to cause cell death by mitochondrial damage. We hypothesized that VacA might disrupt other signaling pathways; to that end, we examined the effects of VacA on MAPKs to elucidate their role in the abnormalities seen in VacA-treated cells. VacA stimulated phosphorylation of p38 and Erk1/2, but not JNK, in AZ-521 cells. Both phosphorylation and kinase activation of p38 were maximal 10-30 min after addition of VacA and declined thereafter. Treatment with anti-VacA antibody or the p38 inhibitor SB203580 blocked p38 phosphorylation caused by VacA and inhibited VacA-induced phosphorylation of activating transcription factor 2 (ATF-2), which is implicated in transcriptional control of stress-responsive genes. These data indicate that VacA stimulates a p38/ ATF-2-mediated signal pathway. However, 10 muM SB203580, which is sufficient to decrease p38 phosphorylation, did not inhibit VacA-induced cellular vacuolation, decrease in mitochondrial membrane potential, or cytochrome c release from mitochondria. These results suggest that VacA-induced activation of p38/ATF-2-mediated signal pathway is independent of cellular vacuolation, decrease in mitochondrial membrane potential, or cytochrome c release from mitochondria caused by VacA. The cytotoxin may thus act independently on several cellular targets, leading to disruption of signaling, regulatory, and metabolic pathways.