Differential activation of mitogen-activated protein kinases in AGS gastric epithelial cells by cag+ and cag- Helicobacter pylori

The aim of this study was to determine whether Helicobacter pylori activates mitogen-activated protein (MAP) kinases in gastric epithelial cells. Infection of AGS cells with an H. pylori cag(+) strain rapidly; (5 min) induced a dose-dependent activation of extracellular signal-regulated kinases (ERK), p38, and c-Jun N-terminal kinase (JNK) MAP kinases, as determined by Western blot analysis and in vitro kinase assay. Compared with cag+ strains, cag(-) clinical isolates were less potent in inducing MAP kinase, particularly JNK and p38, activation. Isogenic inactivation of the picB region of the cag pathogenicity. island resulted in a similar loss of JNK; and p38 MAP kinase activation, The specific MAP kinase inhibitors, PD98059 (25 mu M; MAP kinase kinase (MEK-1) inhibitor) and SB203580 (10 mu M; p38 inhibitor), reduced H. pylori-induced IL-8 production in AGS cells by 78 and 82%, respectively (p < 0.01 for each). Both inhibitors together completely blocked IL-8 production (p < 0,001), However, the MAP kinase inhibitors did not prevent H. pylori-induced I kappa B alpha degradation or NF-kappa B activation, Thus, H. pylori rapidly activates ERK, p38, and JNK MAP kinases in gastric epithelial cells; cag(+) isolates are more potent than cag(-) strains in inducing MAP kinase phosphorylation and gene products of the cog pathogenicity island are required for maximal MAP kinase activation p,78 and MEK-1 activity are required for H, pylori-induced IL-8 production, but do not appear to be essential for H. pylori-induced NF-kappa B activation. Since MAP kinases regulate cell proliferation, differentiation, programmed death, stress, and inflammatory responses, activation of gastric epithelial cell MAP kinases by H, pylori cag(+) strains may be instrumental in inducing gastroduodenal inflammation, ulceration and neoplasia.