Helicobacter pylori induces gastric epithelial cell apoptosis in association with increased Fas receptor expression

The mechanisms involved in mediating the enhanced gastric epithelial cell a poptosis observed during infection with Helicobacter pylori in vivo are unk nown. To determine whether H. pylori directly induces apoptosis of gastric epithelial cells in vitro and to define the role of the Fas-Fas ligand sign al transduction cascade, human gastric epithelial cells were infected with H. pylori for up to 72 h under microaerophilic conditions. As assessed by b oth transmission electron microscopy and fluorescence microscopy, incubatio n with a cagA-positive, cagE-positive, VacA-positive clinical H. pylori iso late stimulated an increase in apoptosis compared to the apoptosis of untre ated AGS cells (16.0% +/- 2.8% versus 5.9% +/- 1.4%, P < 0.05) after 72 h. In contrast, apoptosis was not detected following infection with cagA-negat ive, cagE-negative, VacA-negative clinical isolates or a Campylobacter jeju ni strain. In addition to stimulating apoptosis, infection with H. pylori e nhanced Fas receptor expression in AGS cells to a degree comparable to that of treatment with a positive control, gamma interferon (12.5 ng/ml) (148% +/- 24% and 167% +/- 24% of control, respectively). The enhanced Fas recept or expression was associated with increased sensitivity to Fas-mediated cel l death. Ligation of the Fas receptor with an agonistic monoclonal antibody resulted in an increase in apoptosis compared to the apoptosis of cells in fected with the bacterium alone (38.5% +/- 7.1% versus 16.0% +/- 2.8%, P < 0.05). Incubation with neutralizing anti-Fas antibody did not prevent apopt osis of H. pylori-infected cells. Taken together, these findings demonstrat e that the gastric pathogen H. pylori stimulates apoptosis of gastric epith elial cells in vitro in association with the enhanced expression of the Fas receptor. These data indicate a role for Fas-mediated signaling in the pro grammed cell death that occurs in response to H, pylori infection.