Low pH and Helicobacter pylori increase nuclear factor kappa B binding in gastric epithelial cells: a common pathway for epithelial cell injury?
Helicobacter pylori infection results in peptic ulceration and chronic gastritis through mechanisms which are not fully elucidated. Live H. pylori activate the pro-inflammatory transcription factor NF-kappaB in gastric epithelial cells. Patients may have peptic ulcer disease in the absence of H. pylori infection; therefore other factors contribute to the inflammatory process. Maximal acid output in patients with H. pylori infection and duodenal ulceration is significantly increased indicating a role for acid in the pathogenesis of mucosal ulceration. The effect of low pH on NF-kappaB activation in gastric epithelial cells has not been studied. Human gastric epithelial cells (AGS) were exposed to a range of pH changes in the presence or absence of H. pylori. NF-kappaB DNA-binding and cytosolic IkappaB-alpha were measured using electrophoretic mobility shift assay and Western blotting. NF-kappaB DNA-binding in gastric epithelial cells dramatically increased when the pH of the culture medium decreased. Increases in NF-kappaB nuclear binding were paralleled by decreasing amounts of cytosolic IkappaB-alpha. These findings were similar but less potent than those observed when cells were exposed to H. pylori. Low pH resulted in enhancement of H. pylori-induced NF-kappaB nuclear binding. DNA binding of NF-kappaB activation secondary to low pH was attenuated by PD98059 but not by SB203580. Similar to H. pylori, low pH potently and independently augments NF-kappaB nuclear binding in AGS cells and such activation appears to be mediated through MEK1-dependant signaling pathways.
O'Toole
Dermot
D
Department of Clinical Medicine, Trinity Centre for Health Sciences, St. James's Hospital, Dublin 8, Ireland.
Abdel-Latif
Mohamed M M
MM
Long
Aideen
A
Windle
Henry J
HJ
Murphy
Anne M
AM
Bowie
Andrew
A
O'Neill
Luke A J
LA
Weir
Donald G
DG
Kelleher
Dermot
D
D002470:Cell Survival; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D005753:Gastric Mucosa / Q000166:cytology*; D016481:Helicobacter Infections; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000378:metabolism
D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D020928:Mitogen-Activated Protein Kinases