Activation of activator protein 1 and stress response kinases in epithelial cells colonized by Helicobacter pylori encoding the cag pathogenicity island.
Helicobacter pylori interacts with the apical membrane of the gastric epithelium and induces a number of proinflammatory cytokines/chemokines. The subsequent infiltration of macrophages and granulocytes into the mucosa leads to gastric inflammation accompanied by epithelial degeneration. Gastric diseases, e.g. peptic ulcer or gastric adenocarcinoma, are more common among people infected with H. pylori strains producing VacA (vacuolating cytotoxin A) and possessing a cag (cytotoxin-associated antigen A) pathogenicity island. For the induction of the cytokine/chemokine genes in response to H. pylori, we studied the signaling leading to the nuclear activation of the early response transcription factor activator protein 1 (AP-1). We found that H. pylori strains carrying the pathogenicity island induce activation of AP-1 and nuclear factor kappaB. In contrast to the wild type or an isogenic strain without the vacA gene, isogenic H. pylori strains with mutations in certain cag genes revealed only weak AP-1 and nuclear factor kappaB activation. In respect to the molecular components that direct AP-1 activity, our results indicate a cascade of the cellular stress response kinases c-Jun N-terminal kinase, MAP kinase kinase 4, and p21-activated kinase, and small Rho-GTPases including Rac1 and Cdc42, which contributes to the activation of proinflammatory cytokines/chemokines induced by H. pylori encoding the cag pathogenicity island.
Naumann
M
M
Max-Planck-Institut für Infektionsbiologie, Abteilung Molekulare Biologie, 10117 Berlin, Germany. naumann@mpiib-berlin.mpg.de
Wessler
S
S
Bartsch
C
C
Wieland
B
B
Covacci
A
A
Haas
R
R
Meyer
T F
TF
D000942:Antigens, Bacterial; D001426:Bacterial Proteins / Q000235:genetics*; D001427:Bacterial Toxins / Q000494:pharmacology; D004269:DNA, Bacterial; D005753:Gastric Mucosa / Q000378:metabolism / Q000382:microbiology*; D016480:Helicobacter pylori / Q000235:genetics / Q000472:pathogenicity*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation; D014774:Virulence / Q000235:genetics; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004269:DNA, Bacterial; D016328:NF-kappa B; D018808:Transcription Factor AP-1; C080866:cagA protein, Helicobacter pylori; C031815:toxB protein, Clostridium difficile; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein