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Analysis of apoptotic and antiapoptotic signalling pathways induced by Helicobacter pylori

Department of Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

Correspondence to:
S Maeda, Department of Gastroenterology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo113-8655, Japan;
MAEDA-2IM{at}h.u-tokyo.ac.jp

Background and aims: Although it is reported that Helicobacter pylori induces apoptosis on gastric epithelial cells, the mechanism remains unknown. Antiapoptotic effects generated by H pylori have not yet been evaluated.

Methods: (1) H pylori strains (type 1 wild, TN2-cagE, TN2-vacA) were cocultured with MKN45, TMK1, and HeLa cells, and cell viability and apoptosis were assessed by trypan blue exclusion and DNA laddering, respectively. (2) Activation of caspases-3, 7, and 8, cytochrome c release from the mitochondria, and Fas, Fas associated death domain protein (FADD), Bax, Bak, and Bcl-X expression were evaluated by immunoblot analysis. (3) To investigate whether nuclear factor kappa B (NFB) activation induced by cag pathogenicity island (PAI) positive H pylori affects antiapoptosis, MKN45 cells stably expressing super-repressor IB were cocultured with H pylori, and cell viability and caspase activation were evaluated. NFB regulated gene expression was also evaluated by ribonuclease protection assay.

Results: (1) Wild-type and vacA mutant H pylori induced apoptosis more potently than the cagE mutant. Inhibition of cell contact between H pylori and cancer cells and heat killing H pylori diminished cell death. (2) Caspases-3, 7, and 8 were activated time dependently by H pylori as well as by the agonist anti-Fas. Cytochrome c release from mitochondria was observed and was not inhibited by caspase-8 inhibitor. Although protein expression of Fas, FADD, Bax, Bak, and Bcl-X in the whole cell lysates was not changed by H pylori, Bax was decreased from mitochondria free cytosol suggesting that Bax was translocated into mitochondria. (3) Cell death and the activities of caspases-3 and 8 were promoted in MKN45 cells stably expressing super-repressor IB that inhibits NFB activation. Antiapoptotic proteins c-IAP1 and c-IAP2 were upregulated by the wild-type strains.

Conclusion: cag PAI positive H pylori is capable of inducing apoptotic effects mainly through the mitochondrial pathway. Antiapoptotic effects mediated by NFB activation were also observed.

Keywords: Helicobacter pylori; apoptosis; antiapoptosis; signalling pathway

Abbreviations: PAI, pathogenicity island; NFB, nuclear factor kappa B; FADD, Fas associated death domain protein; IFN, interferon; PBS, phosphate buffered saline; BSA, bovine serum albumin; VacA, vacuolating cytotoxin; FBS, fetal bovine serum; MyD88, myeloid differentiation factor 88

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