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- Title
Helicobacter pylori-induced inhibition of H,K-ATPase α subunit gene expression is mediated by NF-κB.
- Authors
Saha, Arindam; Hammond, Charles E.; Smolka, Adam J.
- Abstract
H. pylori inhibits H,K-ATPase α subunit (HKα) gene expression in gastric epithelial cells, and is also known to activate NF-κB which up-regulates IL-8 gene expression. We tested the hypothesis that H. pylori-induced transcriptional inhibition of HKα is mediated by NF-κB. Human gastric adenocarcinoma (AGS) cell nuclear extracts showed an H. pylori-dependent (25 MOI) consensus NF-κB-binding DNA sequence:protein complex by EMSA. NF-κB p50 antibody supershifts confirmed the protein to be NF-κB. H. pylori infection of AGS cells transfected with an NF-κB-responsive promoter-Luc reporter construct caused a 48% increase in promoter activity, indicating increased NF-κB functional activation in response to H. pylori. DNase-I footprinting identified two NF-κB binding sites (-205 to -187 nt and -170 to -117 nt) on the HKα 5′-flanking sequence. AGS cell transfection of a 226 bp HKα promoter-Luc reporter construct encompassing the NF-κB footprint region caused an H. pylori-dependent 54% inhibition of HKα promoter activity, which was blocked by 10 mM PDTC or 50 µM PD-98059 but not with 10 µM SB-203580 or 100 nM JNK Inhibitor II. We conclude that H. pylori augments NF-κB functional activation in gastric epithelial cells; that NF-κB binds to two sites on HKα 5′-flanking sequence; and that H. pylori-mediated transcriptional down-regulation of HKα occurs through ERK-1/2-dependent NF-κB activation.
- Subjects
HELICOBACTER pylori; HYDROGEN/POTASSIUM ATPase; GENE expression; EPITHELIAL cells; ADENOCARCINOMA; NF-kappa B; HELICOBACTER pylori infections; PROMOTERS (Genetics)
- Publication
FASEB Journal, 2007, Vol 21, Issue 6, pA1317
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fasebj.21.6.a1317-a