title: Differential activation of mitogen-activated protein kinases in AGS gastric epithelial cells by cag+ and cag- Helicobacter pylori.
abstract: 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 microM; MAP kinase kinase (MEK-1) inhibitor) and SB203580 (10 microM; 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 IkappaBalpha degradation or NF-kappaB 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 cag pathogenicity island are required for maximal MAP kinase activation. p38 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-kappaB 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.
authors.affiliation: Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: S
authors.initials: S
authors.lastname: Keates
authors.forename: A C
authors.initials: AC
authors.lastname: Keates
authors.forename: M
authors.initials: M
authors.lastname: Warny
authors.forename: R M
authors.initials: RM
authors.lastname: Peek
authors.forename: P G
authors.initials: PG
authors.lastname: Murray
authors.forename: C P
authors.initials: CP
authors.lastname: Kelly
mesh_terms: D000942:Antigens, Bacterial; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000201:enzymology* / Q000382:microbiology*; D005419:Flavonoids / Q000494:pharmacology; D005753:Gastric Mucosa / Q000201:enzymology* / Q000382:microbiology*; D016480:Helicobacter pylori / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins; D007093:Imidazoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D020672:I-kappa B Proteins; D007093:Imidazoles; D016209:Interleukin-8; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C103937:PicB protein, Helicobacter pylori; D011725:Pyridines; C080866:cagA protein, Helicobacter pylori; D000072000:NF-KappaB Inhibitor alpha; D020928:Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one