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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.

This article has been cited by other articles:

				A. Saha, C. E. Hammond, M. Gooz, and A. J. Smolka The role of Sp1 in IL-1{beta} and H. pylori-mediated regulation of H,K-ATPase gene transcription Am J Physiol Gastrointest Liver Physiol, November 1, 2008; 295(5): G977 - G986. [Abstract] [Full Text] [PDF]