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This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/G795    most recent 00431.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Saha, A. Articles by Smolka, A. J. PubMed PubMed Citation Articles by Saha, A. Articles by Smolka, A. J.

MUCOSAL BIOLOGY

Helicobacter pylori-induced H,K-ATPase -subunit gene repression is mediated by NF-B p50 homodimer promoter binding

Department of Medicine, Medical University of South Carolina, Charleston, South Carolina

Submitted 15 August 2007 ; accepted in final form 17 January 2008

Infection of human gastric body mucosa by the gram-negative, microaerophilic bacterium Helicobacter pylori induces an inflammatory response and a transitory hypochlorhydria that progresses in 2% of patients to atrophic gastritis, dysplasia, and gastric adenocarcinoma. We have previously shown that H. pylori infection of cultured gastric epithelial cells (AGS) represses the activity of the transfected -subunit (HK) promoter of H,K-ATPase, the parietal cell enzyme mediating acid secretion. However, the mechanistic details of H. pylori-mediated repression of HK and ensuing hypochlorhydria are unknown. H. pylori is known to upregulate the transcription factor NF-B through the ERK1/2 MAPK pathway. We identified NF-B-binding regions in the HK promoter and found that H. pylori inoculation of AGS cells increased NF-B p50 binding to the transfected HK promoter and repressed its transcriptional activity. Immunoblot and DNA-protein interaction studies showed that although active phosphorylated NF-B p65 is present in H. pylori-infected AGS cells, an NF-B p50/p65 heterodimeric complex fails to bind to the HK promoter. Point mutations at –159 and –161 bp in the HK promoter NF-B binding sequence prevented binding of NF-B p50 and prevented H. pylori repression of point-mutated HK promoter activity in transfected AGS cells. Small interfering RNA-mediated knockdown of NF-B p50 in H. pylori-infected AGS cells also abrogated H. pylori-induced HK repression, whereas NF-B p65 knockdown did not. We conclude that H. pylori inhibits HK gene expression by ERK1/2-mediated NF-B p50 homodimer binding to the HK promoter. This study identifies a novel pathogen-dependent mechanism of H,K-ATPase inhibition and contributes to understanding of H. pylori pathophysiology.