Skip to main content

How Helicobacter pylori infection controls gastric acid secretion

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.

This is a preview of subscription content, access via your institution.

Fig. 1

References

  1. 1.

    Amieva MR, El-Omar EM. Host-bacterial interactions in Helicobacter pylori infection. Gastroenterology. 2008;134:306–23.

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Atherton JC, Blaser MJ. Coadaptation of Helicobacter pylori and humans: ancient history, modern implications. J Clin Invest. 2009;119(9):2475–87.

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Polk DB, Peek RM. Helicobacter pylori: gastric cancer and beyond. Nat Rev Cancer. 2010;10(6):403–14.

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Linz B, et al. An African origin for the intimate association between humans and Helicobacter pylori. Nature. 2007;445(7130):915–8.

    PubMed  Article  Google Scholar 

  5. 5.

    Dixon MF, et al. Classification and grading of gastritis. The updated Sydney System. International workshop on the histopathology of gastritis, Houston 1994. Am J Surg Pathol. 1996;20(10):1161–81.

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Marshall BJ, et al. Attempt to fulfil Koch’s postulates for pyloric Campylobacter. Med J Aust. 1985;142(8):436–9.

    PubMed  CAS  Google Scholar 

  7. 7.

    Morris A, Nicholson G. Ingestion of Campylobacter pyloridis causes gastritis and raised fasting gastric pH. Am J Gastroenterol. 1987;82(3):192–9.

    PubMed  CAS  Google Scholar 

  8. 8.

    Graham DY, et al. Iatrogenic Campylobacter pylori infection is a cause of epidemic achlorhydria. Am J Gastroenterol. 1988;83(9):974–80.

    PubMed  CAS  Google Scholar 

  9. 9.

    Sobala GM, et al. Acute Helicobacter pylori infection: clinical features, local and systemic immune response, gastric mucosal histology, and gastric juice ascorbic acid concentrations. Gut. 1991;32(11):1415–8.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Ramsey EJ, et al. Epidemic gastritis with hypochlorhydria. Gastroenterology. 1979;76(6):1449–57.

    PubMed  CAS  Google Scholar 

  11. 11.

    El-Omar EM, et al. Helicobacter pylori infection and chronic gastric acid hyposecretion. Gastroenterology. 1997;113(1):15–24.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Harford WV, et al. Acute gastritis with hypochlorhydria: report of 35 cases with long term follow up. Gut. 2000;47(4):467–72.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Sonnenberg A, et al. Hypochlorhydrie bei akuter gastritis. Dtsch Med Wochenschr. 1979;104(51):1814–6.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Takashima M, et al. Effects of Helicobacter pylori infection on gastric acid secretion and serum gastrin levels in Mongolian gerbils. Gut. 2001;48(6):765–73.

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Defize J, Goldie J, Hunt RH. Inhibition of acid production by Campylobacter pylori in isolated guinea pig parietal cells. Am J Gastroenterol. 1989;96:A114.

    Google Scholar 

  16. 16.

    Cave DR, Vargas M. Effect of a Campylobacter pylori protein on acid secretion by parietal cells. Lancet. 1989;2(8656):187–9.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Hoffman JS, et al. Rabbit and ferret parietal cell inhibition by Helicobacter species. Dig Dis Sci. 1995;40(1):147–52.

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Chen XG, et al. Ultrastructure of the gastric mucosa harboring Campylobacter-like organisms. Am J Clin Pathol. 1986;86(5):575–82.

    PubMed  CAS  Google Scholar 

  19. 19.

    Bjorkholm B, et al. Helicobacter pylori entry into human gastric epithelial cells: a potential determinant of virulence, persistence, and treatment failures. Helicobacter. 2000;5(3):148–54.

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Tagkalidis PP, et al. Selective colonization by Helicobacter pylori of the deep gastric glands and intracellular canaliculi of parietal cells in the setting of chronic proton pump inhibitor use. Eur J Gastroenterol Hepatol. 2002;14(4):453–6.

    PubMed  Article  Google Scholar 

  21. 21.

    Tricottet V, et al. Campylobacter-like organisms and surface epithelium abnormalities in active, chronic gastritis in humans: an ultrastructural study. Ultrastruct Pathol. 1986;10(2):113–22.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Lee A, et al. Role of Helicobacter felis in chronic canine gastritis. Vet Pathol. 1992;29(6):487–94.

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Fox JG, et al. Role of gastric pH in isolation of Helicobacter mustelae from the feces of ferrets. Gastroenterology. 1993;104(1):86–92.

    PubMed  CAS  Google Scholar 

  24. 24.

    Kobayashi H, et al. The effect of Helicobacter pylori on gastric acid secretion by isolated parietal cells from a guinea pig. Association with production of vacuolating toxin by H. pylori. Scand J Gastroenterol. 1996;31(5):428–33.

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Jablonowski H, et al. Effects of Helicobacter pylori on histamine and carbachol stimulated acid secretion by human parietal cells. Gut. 1994;35(6):755–7.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Jablonowski H, et al. Effect of Helicobacter pylori on dibutyryl c-AMP-stimulated acid secretion by human parietal cells. Hepatogastroenterology. 1994;41(6):546–8.

    PubMed  CAS  Google Scholar 

  27. 27.

    Furuta T, et al. H+/K+-adenosine triphosphatase mRNA in gastric fundic gland mucosa in patients infected with Helicobacter pylori. Scand J Gastroenterol. 1999;34(4):384–90.

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Plottel CS, Blaser MJ. Microbiome and malignancy. Cell Host Microbe. 2011;10(4):324–35.

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Zavros Y, et al. Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma. Oncogene. 2005;24(14):2354–66.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Spicer Z, et al. Stomachs of mice lacking the gastric H,K-ATPase alpha -subunit have achlorhydria, abnormal parietal cells, and ciliated metaplasia. J Biol Chem. 2000;275(28):21555–65.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Forte JG, et al. Pumps and pathways for gastric HCl secretion. Ann N Y Acad Sci. 1989;574:145–58.

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Sachs G. The gastric proton pump: the H+,K+-ATPase. In: Johnson LR, editor, Physiology of the gastrointestinal tract. . New York: Raven; 1987. p. 865–881.

  33. 33.

    Black JA, Forte TM, Forte JG. Structure of oxyntic cell membranes during conditions of rest and secretion of HCl as revealed by freeze-fracture. Anat Rec. 1980;196(2):163–72.

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Smolka A, Helander HF, Sachs G. Monoclonal antibodies against gastric H+ + K+ATPase. Am J Physiol. 1983;245:589–96.

    Google Scholar 

  35. 35.

    Soroka CJ, et al. Characterization of membrane and cytoskeletal compartments in cultured parietal cells: immunofluorescence and confocal microscopic examination. Eur J Cell Biol. 1993;60(1):76–87.

    PubMed  CAS  Google Scholar 

  36. 36.

    Roepke TK, et al. The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion. J Biol Chem. 2006;281(33):23740–7.

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Song P, et al. KCNQ1 is the luminal K+ recycling channel during stimulation of gastric acid secretion. J Physiol. 2009;587(Pt 15):3955–65.

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Song P, et al. Kir4.1 channel expression is essential for parietal cell control of acid secretion. J Biol Chem. 2011;286(16):14120–8.

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Del Valle J, Sugano K, Yamada T. Progastrin and its glycine-extended posttranslational processing intermediates in human gastrointestinal tissues. Gastroenterology. 1987;92(6):1908–12.

    PubMed  Google Scholar 

  40. 40.

    Beales I, et al. Effect of Helicobacter pylori products and recombinant cytokines on gastrin release from cultured canine G cells. Gastroenterology. 1997;113(2):465–71.

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Delvalle J, et al. Characterization of H2 histamine receptor: linkage to both adenylate cyclase and [Ca2+]i signaling systems. Am J Physiol. 1992;263(6 Pt 1):G967–72.

    PubMed  CAS  Google Scholar 

  42. 42.

    Seal A, et al. Somatostatin-14 and -28: clearance and potency on gastric function in dogs. Am J Physiol. 1982;243(2):G97–102.

    PubMed  CAS  Google Scholar 

  43. 43.

    Li P, Chang TM, Chey WY. Secretin inhibits gastric acid secretion via a vagal afferent pathway in rats. Am J Physiol Gastrointest Liver Physiol. 1998;275(1):G22–8.

    CAS  Google Scholar 

  44. 44.

    Wallace JL, et al. Secretagogue-specific effects of interleukin-1 on gastric acid secretion. Am J Physiol. 1991;261(4 Pt 1):G559–64.

    PubMed  CAS  Google Scholar 

  45. 45.

    Gooz M, et al. Inhibition of human gastric H(+)–K(+)-ATPase alpha-subunit gene expression by Helicobacter pylori. Am J Physiol Gastrointest Liver Physiol. 2000;278(6):G981–91.

    PubMed  CAS  Google Scholar 

  46. 46.

    Mills JC, et al. A molecular profile of the mouse gastric parietal cell with and without exposure to Helicobacter pylori. Proc Natl Acad Sci USA. 2001;98(24):13687–92.

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Saha A, et al. IL-1beta modulation of H,K-ATPase {alpha}-subunit gene transcription in Helicobacter pylori infection. Am J Physiol Gastrointest Liver Physiol. 2007;292(4):G1055–61.

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Saha A, et al. Helicobacter pylori-induced H,K-ATPase {alpha}-subunit gene repression is mediated by NF-{kappa}B p50 homodimer promoter binding. Am J Physiol Gastrointest Liver Physiol. 2008;294(3):G795–807.

    PubMed  Article  CAS  Google Scholar 

  49. 49.

    Saha A, et al. The role of Sp1 in IL-1beta and H. pylori-mediated regulation of H,K-ATPase gene transcription. Am J Physiol Gastrointest Liver Physiol. 2008;295(5):G977–86.

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Saha A, et al. Helicobacter pylori represses proton pump expression and inhibits acid secretion in human gastric mucosa. Gut. 2010;59(7):874–81.

    PubMed  Article  CAS  Google Scholar 

  51. 51.

    Saha A, et al. Helicobacter pylori CagL activates ADAM17 to induce repression of the gastric H,K-ATPase alpha subunit. Gastroenterology. 2010;139(1):239–48.

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Campbell VW, Yamada T. Acid secretagogue-induced stimulation of gastric parietal cell gene expression. J Biol Chem. 1989;264(19):11381–6.

    PubMed  CAS  Google Scholar 

  53. 53.

    Campbell VW, Yamada T. Effect of omeprazole on gene expression in canine gastric parietal cells. Am J Physiol. 1991;260(3 Pt 1):G434–9.

    PubMed  CAS  Google Scholar 

  54. 54.

    Nishi T, et al. Transcriptional activation of H+/K+-ATPase genes by gastric GATA binding proteins. J Biochem (Tokyo). 1997;121(5):922–9.

    Article  CAS  Google Scholar 

  55. 55.

    Tamura S, et al. Gastric DNA-binding proteins recognize upstream sequence motifs of parietal cell-specific genes [published erratum appears in Proc Natl Acad Sci USA 1994 May 10;91(10):4609]. Proc Natl Acad Sci USA. 1993;90(22):10876–80.

    PubMed  Article  CAS  Google Scholar 

  56. 56.

    Muraoka A, et al. Canine H(+)–K(+)-ATPase alpha-subunit gene promoter: studies with canine parietal cells in primary culture. Am J Physiol. 1996;271(6 Pt 1):G1104–13.

    PubMed  CAS  Google Scholar 

  57. 57.

    Kaise M, et al. Epidermal growth factor induces H+,K+-ATPase alpha-subunit gene expression through an element homologous to the 3′ half-site of the c-fos serum response element. J Biol Chem. 1995;270(31):18637–42.

    PubMed  Article  CAS  Google Scholar 

  58. 58.

    Dubois A, et al. Natural gastric infection with Helicobacter pylori in monkeys: a model for spiral bacteria infection in humans. Gastroenterology. 1994;106(6):1405–17.

    PubMed  CAS  Google Scholar 

  59. 59.

    Viala J, et al. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol. 2004;5(11):1166–74.

    PubMed  Article  CAS  Google Scholar 

  60. 60.

    Backert S, Selbach M. Role of type IV secretion in Helicobacter pylori pathogenesis. Cell Microbiol. 2008;10(8):1573–81.

    PubMed  Article  CAS  Google Scholar 

  61. 61.

    Backert S, Clyne M, Tegtmeyer N. Molecular mechanisms of gastric epithelial cell adhesion and injection of CagA by Helicobacter pylori. Cell Commun Signal. 2011;9(1):28.

    PubMed  Article  CAS  Google Scholar 

  62. 62.

    Ruoslahti E. RGD and other recognition sequences for integrins. Ann Rev Cell Dev Biol. 1996;12:697–715.

    Article  CAS  Google Scholar 

  63. 63.

    Covacci A, Rappuoli R. Tyrosine-phosphorylated bacterial proteins: Trojan horses for the host cell. J Exp Med. 2000;191(4):587–92.

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    Kwok T, et al. Helicobacter exploits integrin for type IV secretion and kinase activation. Nature. 2007;449(7164):862–6.

    PubMed  Article  CAS  Google Scholar 

  65. 65.

    Kim H, Lim JW, Kim KH. Helicobacter pylori-induced expression of interleukin-8 and cyclooxygenase-2 in AGS gastric epithelial cells: mediation by nuclear factor-kappaB. Scand J Gastroenterol. 2001;36(7):706–16.

    PubMed  Article  CAS  Google Scholar 

  66. 66.

    Schlondorff J, Blobel CP. Metalloprotease-disintegrins: modular proteins capable of promoting cell–cell interactions and triggering signals by protein-ectodomain shedding. J Cell Sci. 1999;112(Pt 21):3603–17.

    PubMed  CAS  Google Scholar 

  67. 67.

    Bridges LC, Bowditch RD. ADAM-integrin interactions: potential integrin regulated ectodomain shedding activity. Curr Pharm Des. 2005;11(7):837–47.

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Tegtmeyer N, et al. A small fibronectin-mimicking protein from bacteria induces cell spreading and focal adhesion formation. J Biol Chem. 2010;285(30):23515–26.

    PubMed  Article  CAS  Google Scholar 

  69. 69.

    Lichtenberger LM, Delansorne R, Graziani LA. Importance of amino acid uptake and decarboxylation in gastrin release from isolated G cells. Nature. 1982;295(5851):698–700.

    PubMed  Article  CAS  Google Scholar 

  70. 70.

    Zanner R, et al. Intracellular signal transduction during gastrin-induced histamine secretion in rat gastric ECL cells. Am J Physiol Cell Physiol. 2002;282(2):C374–82.

    PubMed  CAS  Google Scholar 

  71. 71.

    Tucker TP, et al. Helicobacter pylori induction of the gastrin promoter through GC-rich DNA elements. Helicobacter. 2010;15(5):438–48.

    PubMed  Article  CAS  Google Scholar 

  72. 72.

    Wiedemann T, et al. Helicobacter pylori CagL dependent induction of gastrin expression via a novel αvβ5-integrin-integrin linked kinase signalling complex. Gut 2012;in press.

  73. 73.

    Mimuro H, et al. Grb2 is a key mediator of Helicobacter pylori CagA protein activities. Mol Cell. 2002;10(4):745–55.

    PubMed  Article  CAS  Google Scholar 

  74. 74.

    Brandt S, et al. NF-kappaB activation and potentiation of proinflammatory responses by the Helicobacter pylori CagA protein. Proc Natl Acad Sci USA. 2005;102(26):9300–5.

    PubMed  Article  CAS  Google Scholar 

  75. 75.

    Keates S, et al. cag+ Helicobacter pylori induces transactivation of the epidermal growth factor receptor in AGS gastric epithelial cells. J Biol Chem. 2001;276(51):48127–34.

    PubMed  CAS  Google Scholar 

  76. 76.

    Nozawa Y, et al. Identification of a signaling cascade for interleukin-8 production by Helicobacter pylori in human gastric epithelial cells. Biochem Pharmacol. 2002;64(1):21–30.

    PubMed  Article  CAS  Google Scholar 

  77. 77.

    Hirata Y, et al. Helicobacter pylori CagA protein activates serum response element-driven transcription independently of tyrosine phosphorylation. Gastroenterology. 2002;123(6):1962–71.

    PubMed  Article  CAS  Google Scholar 

  78. 78.

    Suzuki M, et al. Helicobacter pylori CagA phosphorylation-independent function in epithelial proliferation and inflammation. Cell Host Microbe. 2009;5(1):23–34.

    PubMed  Article  CAS  Google Scholar 

  79. 79.

    Lamb A, et al. Helicobacter pylori CagA activates NF-kappaB by targeting TAK1 for TRAF6-mediated Lys 63 ubiquitination. EMBO Rep. 2009;10(11):1242–9.

    PubMed  Article  CAS  Google Scholar 

  80. 80.

    Hirata Y, et al. MyD88 and TNF receptor-associated factor 6 are critical signal transducers in Helicobacter pylori-infected human epithelial cells. J Immunol. 2006;176(6):3796–803.

    PubMed  CAS  Google Scholar 

  81. 81.

    Watanabe T, et al. NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway. J Clin Invest. 2010;120(5):1645–62.

    PubMed  Article  CAS  Google Scholar 

  82. 82.

    Blaser MJ, Atherton JC. Helicobacter pylori persistence: biology and disease. J Clin Invest. 2004;113(3):321–33.

    PubMed  CAS  Google Scholar 

  83. 83.

    Telford JL, et al. Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease. J Exp Med. 1994;179(5):1653–8.

    PubMed  Article  CAS  Google Scholar 

  84. 84.

    Cover TL, Blanke SR. Helicobacter pylori VacA, a paradigm for toxin multifunctionality. Nat Rev Microbiol. 2005;3(4):320–32.

    PubMed  Article  CAS  Google Scholar 

  85. 85.

    Nakayama M, et al. Helicobacter pylori VacA activates the p38/activating transcription factor 2-mediated signal pathway in AZ-521 cells. J Biol Chem. 2004;279(8):7024–8.

    PubMed  Article  CAS  Google Scholar 

  86. 86.

    Tegtmeyer N, et al. Importance of EGF receptor, HER2/Neu and Erk1/2 kinase signalling for host cell elongation and scattering induced by the Helicobacter pylori CagA protein: antagonistic effects of the vacuolating cytotoxin VacA. Cell Microbiol. 2009;11(3):488–505.

    PubMed  Article  CAS  Google Scholar 

  87. 87.

    Wang F, et al. Helicobacter pylori VacA disrupts apical membrane-cytoskeletal interactions in gastric parietal cells. J Biol Chem. 2008;283(39):26714–25.

    PubMed  Article  CAS  Google Scholar 

  88. 88.

    Peek RM Jr, et al. Heightened inflammatory response and cytokine expression in vivo to cagA+ Helicobacter pylori strains. Lab Invest. 1995;73(6):760–70.

    PubMed  CAS  Google Scholar 

  89. 89.

    Sharma SA, et al. Interleukin-8 response of gastric epithelial cell lines to Helicobacter pylori stimulation in vitro. Infect Immun. 1995;63(5):1681–7.

    PubMed  CAS  Google Scholar 

  90. 90.

    Yamaoka Y, et al. Helicobacter pylori cagA gene and expression of cytokine messenger RNA in gastric mucosa. Gastroenterology. 1996;110(6):1744–52.

    PubMed  Article  CAS  Google Scholar 

  91. 91.

    Wolfe MM, Nompleggi DJ. Cytokine inhibition of gastric acid secretion—a little goes a long way. Gastroenterology. 1992;102(6):2177–8.

    PubMed  CAS  Google Scholar 

  92. 92.

    Beales IL, Calam J. Interleukin 1 beta and tumour necrosis factor alpha inhibit acid secretion in cultured rabbit parietal cells by multiple pathways. Gut. 1998;42(2):227–34.

    PubMed  Article  CAS  Google Scholar 

  93. 93.

    Schepp W, et al. Identification and functional importance of IL-1 receptors on rat parietal cells. Am J Physiol. 1998;275(5 Pt 1):G1094–105.

    PubMed  CAS  Google Scholar 

  94. 94.

    Peek RM Jr, Blaser MJ. Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer. 2002;2(1):28–37.

    PubMed  Article  CAS  Google Scholar 

  95. 95.

    El-Omar EM, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404(6776):398–402.

    PubMed  Article  CAS  Google Scholar 

  96. 96.

    Keates S, et al. Helicobacter pylori infection activates NF-kappa B in gastric epithelial cells. Gastroenterology. 1997;113(4):1099–109.

    PubMed  Article  CAS  Google Scholar 

  97. 97.

    Perkins ND. Integrating cell-signalling pathways with NF-[kappa]B and IKK function. Nat Rev Mol Cell Biol. 2007;8(1):49–62.

    PubMed  Article  CAS  Google Scholar 

  98. 98.

    Hayden MS, Ghosh S. Signaling to NF-{kappa}B. Genes Dev. 2004;18(18):2195–224.

    PubMed  Article  CAS  Google Scholar 

  99. 99.

    Zhang W, Kone BC. NF-kappaB inhibits transcription of the H(+)–K(+)-ATPase alpha(2)-subunit gene: role of histone deacetylases. Am J Physiol Renal Physiol. 2002;283(5):F904–11.

    PubMed  Google Scholar 

  100. 100.

    Zhong H, et al. The phosphorylation status of nuclear NF-[kappa]B determines its association with CBP/p300 or HDAC-1. Mol Cell. 2002;9(3):625–36.

    PubMed  Article  CAS  Google Scholar 

  101. 101.

    Blaser MJ. Helicobacter pylori and esophageal disease: wake-up call? Gastroenterology. 2010;139(6):1819–22.

    PubMed  Article  Google Scholar 

  102. 102.

    Malfertheiner P, et al. Symposium: Helicobacter pylori and clinical risks—focus on gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2002;16(Suppl 3):1–10.

    PubMed  Article  Google Scholar 

Download references

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.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Adam J. Smolka.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Keywords

  • ADAM17
  • cag pathogenicity island
  • EGFR
  • ERK1/2
  • Gastric adenocarcinoma
  • HB-EGF
  • Helicobacter pylori
  • HKα-ATPase
  • Hypochlorhydria
  • Integrin α5β1
  • Parietal cells
  • Transcription factor NF-κB
  • Type IV secretion system