Toxicity of Helicobacter pylori VacA and its mutual effect with CagA

1) VacA可能通过抑制STAT3下调抗凋亡Bcl-2亚家族蛋白诱导细胞凋亡。2) VacA通过p38 MAPK/ATF-2级联诱导COX-2表达，从而激活COX-2启动子中的CRE位点，从而促进AZ-521细胞产生PGE2。3)在促单核细胞U937细胞中，VacA通过细胞内Ca^<2+>释放激活p38 MAPK，直接增加IL-8的产生，导致转录因子ATF-2、CREB和NF-kB的激活。4) VacA通过激活PI3K刺激蛋白激酶B （Akt）活性，导致其底物GSK3磷酸化增加，随后从GSK3/■-catenin复合物释放■-catenin并将其易位到细胞核，从而激活cyclin D1启动子。5)从幽门螺杆菌转运到胃上皮细胞的CagA通过抑制细胞内吞作用抑制VacA的摄取和细胞毒性。然而，转染cagA基因不影响VacA引起的p38 MAPK的激活。

1) VacA may induce apoptosis by downregulation of anti-apoptotic Bcl-2 subfamily proteins via STAT3 inhibition. 2) VacA enhances PGE2 production by AZ-521 cells through induction of COX-2 expression via the p38 MAPK/ATF-2 cascade, leading to activation of the CRE site in the COX-2 promoter. 3) In promonocytic U937 cells, VacA directly increases IL-8 production by activation of the p38 MAPK via intracellular Ca^<2+> release, leading to activation of the transcription factors, ATF-2, CREB, and NF-kB. 4) VacA stimulated protein kinase B (Akt) activity via activation of PI3K, resulting in increased phosphorylation of its substrate, GSK3, with subsequent release of ■-catenin from a GSK3/■-catenin complex and its translocation to the nucleus, leading to activation of the cyclin D1 promoter. 5) Translocated CagA from H. pylori into gastric epithelial cells inhibit uptake and cytotoxicity of VacA via endocytosis inhibition in the cells. However, transfection of cagA gene did not affect the activation of p38 MAPK caused by VacA.