How Helicobacter pylori infection controls gastric acid secretion

Infection of the human stomach mucosa by Helicobacter pylori induces strong inflammatory responses and a transitory hypochlorhydria which can progress in similar to 2 % of patients to atrophic gastritis, dysplasia, or gastric adenocarcinoma. H. pylori infection of gastric biopsies or cultured gastric epithelial cells in vitro represses the activity of endogenous or transfected promoter of the alpha-subunit (HK alpha) of gastric H,K-adenosine triphosphatase (H,K-ATPase), the parietal cell enzyme mediating acid secretion. Some mechanistic details of H. pylori-mediated repression of HK alpha and ensuing hypochlorhydria have been recently elucidated. H. pylori strains expressing a type IV secretion system (T4SS) encoded by the cag pathogenicity island are known to upregulate the transcription factor nuclear factor (NF)-kappa B. The NF-kappa B-binding regions in the HK alpha promoter were identified and shown to repress its transcriptional activity. Interaction studies have indicated that although active phosphorylated NF-kappa B p65 is present in infected cells, an NF-kappa B p50/p65 heterodimeric complex fails to bind to the HK alpha promoter. Point mutations at -159 and -161 bp in the HK alpha promoter NF-kappa B binding sequence prevent the binding of NF-kappa B p50 and prevent H. pylori repression of point-mutated HK alpha promoter activity. The T4SS factors CagL, CagE, CagM, and possibly CagA and the lytic transglycosylase Slt, are mechanistically involved in NF-kappa B activation and repression of HK alpha transcription. CagL, a T4SS pilus component, binds to the integrin alpha(5)beta(1) to mediate translocation of virulence factors into the host cell and initiate signaling. During acute H. pylori infection, CagL dissociates ADAM 17 (a disintegrin and a metalloprotease 17) from the integrin alpha(5)beta(1) complex and stimulates ADAM17-dependent release of heparin-binding epidermal growth factor (HB-EGF), EGF receptor (EGFR) stimulation, ERK1/2 kinase activation, and NF-kappa B-mediated repression of HK alpha. These studies suggest that H. pylori inhibits HK alpha gene expression by an integrin alpha(5)beta(1) -> ADAM17 -> HB-EGF -> EGFR -> ERK1/2 -> NF-kappa B pathway mediating NF-kappa B p50 homodimer binding to the HK alpha promoter. Here we review the molecular basis and recent progress of this novel pathogen-dependent mechanism of H,K-ATPase inhibition, which contributes significantly to our current understanding of H. pylori pathophysiology.