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How Helicobacter pylori infection controls gastric acid secretion

Journal of Gastroenterology volume 47, pages 609–618 (2012)Cite this article

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Abstract

Infection of the human stomach mucosa by Helicobacter pylori induces strong inflammatory responses and a transitory hypochlorhydria which can progress in ~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 (HKα) 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 HKα 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)-κB. The NF-κB-binding regions in the HKα promoter were identified and shown to repress its transcriptional activity. Interaction studies have indicated that although active phosphorylated NF-κB p65 is present in infected cells, an NF-κB p50/p65 heterodimeric complex fails to bind to the HKα promoter. Point mutations at −159 and −161 bp in the HKα promoter NF-κB binding sequence prevent the binding of NF-κB p50 and prevent H. pylori repression of point-mutated HKα promoter activity. The T4SS factors CagL, CagE, CagM, and possibly CagA and the lytic transglycosylase Slt, are mechanistically involved in NF-κB activation and repression of HKα transcription. CagL, a T4SS pilus component, binds to the integrin α5β1 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 α5β1 complex and stimulates ADAM17-dependent release of heparin-binding epidermal growth factor (HB-EGF), EGF receptor (EGFR) stimulation, ERK1/2 kinase activation, and NF-κB-mediated repression of HKα. These studies suggest that H. pylori inhibits HKα gene expression by an integrin α5β1 → ADAM17 → HB-EGF → EGFR → ERK1/2 → NF-κB pathway mediating NF-κB p50 homodimer binding to the HKα 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.

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Acknowledgments

We thank Dr. Mitchell Schubert for critical reading of the manuscript and for valuable suggestions. This work was supported in part by NIH grant R01DK064371 to A.J. Smolka and by Deutsche Forschungsgemeinschaft (Ba1671/3 and Ba1671/8-1) and Science Foundation Ireland (UCD 09/IN.1/B2609) to S. Backert.

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  1. Department of Medicine, Medicine/Gastro CSB 921E, Medical University of South Carolina, 96 Jonathan Lucas St., Charleston, SC, 29425, USA

    Adam J. Smolka

  2. UCD School of Biomolecular and Biomedical Sciences, University College Dublin, Science Center West L231, Belfield Campus, Dublin 4, Ireland

    Steffen Backert

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Correspondence to Adam J. Smolka.

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Smolka, A.J., Backert, S. How Helicobacter pylori infection controls gastric acid secretion. J Gastroenterol 47, 609–618 (2012). https://doi.org/10.1007/s00535-012-0592-1

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