Apoptosis and the Pathogenesis of Helicobacter pylori—Related Disease

  • Emilia Mia Sordillo
  • Steven F. Moss
Part of the Infectious Agents and Pathogenesis book series (IAPA)


It is an unavoidable, but intriguing, fact that chronic colonization of the stomach by Helicobacter pylori has no obvious deleterious consequences in most people. Approximately 10% of all infected individuals will develop a peptic ulcer, and half of those will commence a slow progression of pre-neoplastic changes that will ultimately lead to frank cancer in only a few.1 Why are certain individuals or populations predisposed to particular clinical outcomes after infection with H. pylori? The genetic background of the individual, the timing of first infection, environmental factors, and variations in the degree of bacterial pathogenicity all may contribute to the outcome of infection. One physiologic process that can be influenced by these variables is apoptosis, which when deregulated causes abnormal cell turnover, alterations in epithelial cell subpopulations, and changes in mucosal mass.


Gastric Cancer Atrophic Gastritis Chronic Gastritis Malt Lymphoma Gastric Epithelial Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Blaser M. J., and Parsonnet J. et al., 1994, Parasitism by the “slow” bacterium Helicobacter pylori leads to altered gastric homeostasis and neoplasia. J. Clin. Invest. 94:4–8PubMedCrossRefGoogle Scholar
  2. 2.
    Zychlinsky A., and Sansonetti P. J. et al., 1997, Apoptosis as a proinflammatory event: What can we learn from bacteria-induced cell death? Trends in Microbiology 5:201–204PubMedCrossRefGoogle Scholar
  3. 3.
    Anti M., Armuzzi A., Gasbarrini A., and Gasbarrini G. et al., 1998, Importance of changes in epithelial cell turnover during Helicobacter pylori infection in gastric carcinogenesis. Gut. 43 (suppl 1):S27–32PubMedCrossRefGoogle Scholar
  4. 4.
    Shirin H., and Moss S. F. et al., 1998, Leading article: Helicobacter pylori-induced apoptosis. Gut. 43:592–594PubMedCrossRefGoogle Scholar
  5. 5.
    Abdalla A. M., Krivosheyev V., Hanzely Z., Holt P. R., Perez-Perez G. I., Blaser M. J., and Moss S. F. et al., 1998, Increased epithelial cell turnover in antrum and corpus of H. pylori-infected stomach, irrespective of GagA status. Gastroenterology 114:A50CrossRefGoogle Scholar
  6. 6.
    Peek R. M., Moss S. F., Tham K. T., Perez-Perez G. I., Miller G. G., Atherton J. C., Holt P. R., and Blaser M.J. et al., 1997, Helicobacter pylori cagA+ strains and dissociation of gastric epithelial proliferation from apoptosis. J. Natl. Cancer Inst. 89:863–868PubMedCrossRefGoogle Scholar
  7. 7.
    Rokkas T., Ladas S., Liatsos G., Petridou E., Papatheodorou G., Theocharis S., Karameris A., and Raptis S. et al., 1999, Relationship of Helicobacter pylori CagA status to gastric cell proliferation and apoptosis. Dig. Dis. Sci. 44: 487–493PubMedCrossRefGoogle Scholar
  8. 8.
    Rudi J., Kuck D., Strand S., von Herbay A., Mariani S. M., Krammer P. H., Galle P. R., and Stremmel W. et al., 1998, Involvement of the GD95 (APO-1/Fas) receptor and ligand system in Helicobacter pylori-induced gastric epithelial apoptosis. J. Clin. Invest. 102:1506–1514PubMedCrossRefGoogle Scholar
  9. 9.
    Houghton J., Korah R. M., Condon M. R., and Kim K. H. et al., 1999, Apoptosis in Helicobacter pylori-associated gastric and duodenal ulcer disease is mediated via the Fas antigen pathway Dig. Dis. Sci. 44:465–478PubMedCrossRefGoogle Scholar
  10. 10.
    Steininger H., Faller G., Dewald E., Brabletz T., Jung A., and Kirchner T. et al., 1998, Apoptosis in chronic gastritis and its correlation with antigastric autoantibodies, only Virchows. Arch. 433:13–18PubMedCrossRefGoogle Scholar
  11. 11.
    Wang T. C., Goldenring J. R., Dangler C., Ito S., Mueller A., Jeon W. K., Koh T. J., and Fox J. G. et al, 1998, Mice lacking secretory phospholipase A2 show altered apoptosis and differentiation with Helicobacterfelis infection. Gastroenterology 114:675—689Google Scholar
  12. 12.
    Syder A. J., Guruge J. L., Li Q., Hu Y., Oleksiewicz C. M., Lorenz R. G., Karam S. M., Falk P. G., and Gordon J. I. et al., 1999, Helicobacter pylori attaches to NeuAc alpha 2,3Gal beta 1,4 glycoconjugates produced in the stomach of transgenic mice lacking parietal cells. Mol. Cell 3:263–274PubMedCrossRefGoogle Scholar
  13. 13.
    Li H., Andersson E.-M., and Helander H. F. et al., 1999, Reactions from rat gastric mucosa during one year of Helicobacter pylori infection. Dig. Dis. Sci. 44:116–124PubMedCrossRefGoogle Scholar
  14. 14.
    Peek R. M., Wirth H. P., Moss S. F., Yang M., Abdalla A. M., Tham K. T., Zhang T., Tang L. H., Modlin I. M., and Blaser M. J. et al., Helicobacter pylori alters gastric epithelial cell cycle events and gastrin secretion in Mongolian gerbils. Gastroenterology (in press).Google Scholar
  15. 15.
    Li M., Mellgard B., and Helander H. F. et al., 1997, Inoculation of VacA- and CagA-Helicobacter pylori delays gastric ulcer healing in the rat. Scand. J. Gastroenterol. 32:439–444PubMedCrossRefGoogle Scholar
  16. 16.
    Piotrowski J., Piotrowski E., Skrodzka D., Slomiany A., and Slomiany B. L. et al., 1997, Induction of acute gastritis and epithelial cell apoptosis by Helicobacter pylori lipopolysaccharide. Scand. J. Gastroenterol. 32:203–211PubMedCrossRefGoogle Scholar
  17. 17.
    Aliprantis A. O., Yang R.-B., Mark M. R., Suggett S., Devaux B., Radolf J. D., Klimpel G. R., Godowski P., and Zychlinsky A. et al., 1999, Cell activation and apoptosis by bacterial lipoproteins through Toll-like receptor-2. Science 285:736–739PubMedCrossRefGoogle Scholar
  18. 18.
    Luo X.-L., Ramanujam K. S., Zhao H.-M., Moss S. F., Russell R. G., Drachenberg C. B., and Wilson K. T. et al., 1999, Protective role of GOX-2 in H. pylori gastritis. Gastroenterology 116:A767Google Scholar
  19. 19.
    Fox J. G., Li X., Cahill R. J., Andrutis K., Rustgi A. K., Odze R., and Wang T. G. et al., 1996, Hypertrophic gastropathy in Helicobacter felis-infected wild-type C57BL/6 mice and p53 hemizy-gous transgenic mice. Gastroenterology 110:155–166PubMedCrossRefGoogle Scholar
  20. 20.
    Lozniewski A., Muhale F., Hatier R., Marais A., Conroy M. C., Edert D., le Faou A., Weber M., and Duprez A. et al., 1999, Human embryonic gastric xenografts in nude mice: a new model of Helicobacter pylori infection. Infect. Immun. 67:1798–1805PubMedGoogle Scholar
  21. 21.
    Crabtree J. E., Farmery S. M., Lindley I. J., Peichl P., and Tompkins D. S. et al., 1994, CagA/cytotoxic strains of Helicobacter pylori and interleukin-8 in gastric epithelial cell lines. J. Clin. Pathol. 47:945–950PubMedCrossRefGoogle Scholar
  22. 22.
    Sharma S. A., Tummuru M. K. R., Miller G. G., and Blaser M. J. et al., 1995, Interleukin-8 response of gastric epithelial cell lines to Helicobacter pylori stimulation in vitro. Infect. Immun. 63:1681–1687PubMedGoogle Scholar
  23. 23.
    Ogura K., Takahashi M., Maeda S., Ikenoue T., Kanai F., Yoshida H., Shiratori Y., Mori K., Mafune K. I., and Ogata M. et al., 1998, Interleukin-8 production in primary cultures of human gastric epithelial cells induced by Helicobacter pylori. Dig. Dis. Sci. 43:2738–2743PubMedCrossRefGoogle Scholar
  24. 24.
    Beales I. L., and Calam J. et al., 1997, Stimulation of IL-8 production in human gastric epithelial cells by Helicobacter pylori, IL-1 beta and TNF-alpha requires tyrosine kinase activity, but not protein kinase G. Cytokine 9:514–520PubMedCrossRefGoogle Scholar
  25. 25.
    Aihara M., Tsuchimoto D., Takizawa H., Azuma A., Wakebe H., Ohmoto Y., Imagawa K., Kikuchi M., Mukaida N., and Matsushima K. et al., 1997, Mechanisms involved in Helicobacter pylori-induced interleukin-8 production by a gastric cancer cell line, MKN45. Infect. Immun. 65:3218–3224PubMedGoogle Scholar
  26. 26.
    Segal E. D., Lange G., Govacci A., Tompkins L. S., and Falkow S. et al., 1997, Induction of host signal transduction pathways by Helicobacter pylori. Proc. Natl. Acad. Sci. USA 94:7595–7599PubMedCrossRefGoogle Scholar
  27. 27.
    Sharma S. A., Tummuru M. K., Blaser M. J., and Kerr L. D. et al., 1998, Activation of IL-8 gene expression by Helicobacter pylori is regulated by transcription factor nuclear kappa B in gastric epithelial cells. J. Immunol. 160:2401–2407PubMedGoogle Scholar
  28. 28.
    Terui Y., Tomizuka H., Mishima Y., Ikeda M., Kasahara T., Uwai M., Mori M., Itoh T., Tanaka M., Yamada M., Shimamura S., Ishizaka Y., Ozawa K., and Hatake K. et al., 1999, Cancer Res. 59:5651–5655PubMedGoogle Scholar
  29. 29.
    Chen G., Sordillo E. M., Ramey W. G., Reidy J., Holt P., Krajewski S., Reed J. C., Blaser M. J., and Moss S. F. et al., 1997, Apoptosis in gastric epithelial cells is induced by Helicobacter pylori and accompanied by increased expression of BAK. Biochem. Biophys. Res. Commun. 239:626–632PubMedCrossRefGoogle Scholar
  30. 30.
    Tummuru M. K., Sharma S. A., and Blaser M. J. et al., 1995, Helicobacter pylori picB, a homologue of the Bordetella pertussis toxin secretion protein, is required for the induction of IL-8 in gastric epithelial cells. Mol. Microbiol. 18:867–876PubMedCrossRefGoogle Scholar
  31. 31.
    Censini S., Lange C., Xiang Z., Crabtree J. E., Ghiara P., Borodovsky M., Rappuoli R., and Covacci A. et al., 1996, cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc. Natl. Acad. Sci. USA 93:14648–14653PubMedCrossRefGoogle Scholar
  32. 32.
    Munzenmaier A., Lange G., Glocker E., Govacci A., Moran A., Bereswill S., Baeuerle P. A., Kist M., and Pahl H. L. et al., 1997, A secreted/shed product of Helicobacter pylori activates transcription factor nuclear factor kappa B. J. Immunol. 159:6140–6147PubMedGoogle Scholar
  33. 33.
    Keates S., Keates A. C., Warney M., Peek R. M., Murray P. G., and Kelly C. P. et al., 1999, Differential activation of mitogen-activated protein-kinases in AGS epithelial cells by cag+ and cag- Helicobacter pylori. J. Immunol. 163:5552–5559PubMedGoogle Scholar
  34. 34.
    Peek R. M., Blaser M. J., Mays D. J., Forsyth M. H., Cover T. L., Song S. Y., Krishnan U., and Pietenpol J. A. et al.,Helicobacter pylori strain-specific genotypes and modulation of the gastric epithelial cell cycle. Cancer Res. (in press)Google Scholar
  35. 35.
    Wagner S., Beil W., Westermann J., Logan R. P., Bock C. T., Trautwein C., Bleck J. S., and Manns M. P. et al., 1997, Regulation of gastric epithelial cell growth by Helicobacter pylori: evidence for a major role of apoptosis. Gastroenterology 113:1836–1847PubMedCrossRefGoogle Scholar
  36. 36.
    Kimura M., Gotot S., Wada A., Yahiro K., Niidome T., Hatakeyama T., Aoyagi H., Hirayama T., and Kondo T et al., 1999, Vacuolating cytotoxin purified from Helicobacter pylori causes mitochondrial damage in human gastric cells. Microb. Pathog. 26:45–52PubMedCrossRefGoogle Scholar
  37. 37.
    Pai R., Cover T. L., and Tarnawski A. S. et al., 1999, Helicobacter pylori vacuolating cytotoxin (VacA) disorganizes the cytoskeletal architecture of gastric epithelial cells. Biochem. Biophys. Res. Commun. 19:245–250Google Scholar
  38. 38.
    Papini E., Satin B., Norais N., deBernard M., Telford J. L., Rappuoli R., and Montecucco C. et al., 1998, Selective increase of the permeability of polarized epithelial cell monolayers by Helicobacter pylori vacuolating toxin. J. Clin. Invest. 102:813–820PubMedCrossRefGoogle Scholar
  39. 39.
    Pellici V., Reyrat J. M., Sartori L., Pagliaccia C., Rappuoli R., Telford J. L., Montecucco C., and Papini E. et al., 1999, Helicobacter pylori VacA cytotoxin associated with the bacteria increases epithelial permeability independently of its vacuolating activity. Microbiology 145:2043–2050CrossRefGoogle Scholar
  40. 40.
    Manetti R., Massari P., Marchetti M., Magagnoli C., Nuti S., Lupetti P., Ghiara P., Rappuoli R., and Telford J. L. et al, 1997, Detoxification of the Helicobacter pylori cytotoxin. Infect. Immun. 65:4615–4619PubMedGoogle Scholar
  41. 41.
    Shibata J., Goto H., Arisawa T., Niwa Y, Hayakawa T., Nakayama A., and Mori N. et al., 1999, Regulation of tumour necrosis factor (TNF) induced apoptosis by soluble TNF receptors in Helicobacter pylori infection. Gut. 45:24—31PubMedCrossRefGoogle Scholar
  42. 42.
    Jones N. L., Day A. S., Jennings H. A., and Shernman P. M. et al.,1999, Helicobacter pylori induces gastric epithelial cell apoptosis in association with increased Fas receptor expression. Infect. Immun. 67:4237–4242PubMedGoogle Scholar
  43. 43.
    Fan X., Crowe S. F., Behar S., Gunasena H., Ye G., Haeberle H., Van Houten N., Gourley W. K., Ernst P. B., and Reyes V. E. et al., 1998, The effect of class II major histocompatibility complex expression on adherence of Helicobacter pylori and induction of apoptosis in gastric epithelial cells: A mechanism for T helper cell type-I mediated damage. J. Exp. Med. 187: 1659–1669PubMedCrossRefGoogle Scholar
  44. 44.
    Konturek P. C., Pierzchalski P., Konturek S. J., Meixner H., Faller G., Kirchner T., and Hahn E. G. et al, 1999, Helicobacter pylori induces apoptosis in gastric mucosa through an upregulation of Bax expression in humans. Scand. J. Gastroenterol. 34:375–383PubMedCrossRefGoogle Scholar
  45. 45.
    Wagner S., Mix H., Sobek-Koocked I., Obst B., Schmidt H., Bleck J., Kirchner G., Gokeb M., Manns M. P., and Beil W. et al., 1999, Activation of caspase-8 and -3 mediates apoptosis in gastric epithelial cells induced by Helicobacter pylori. Gastroenterology 116:347Google Scholar
  46. 46.
    Naumann M. Wessler S., Bartsch C., Wielans B., Covacci A., Haas R., and Meyer T F. et al., 1999, Activation of activator protein-1 and stress response kinases in epithelial cells colonized by Helicobacter pylori encoding the pathogenicity island. J. Biol. Chem. 274:31655–31662PubMedCrossRefGoogle Scholar
  47. 47.
    Wisdom R., Johnson R. S., and Moore C. et al.,1999, c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms. EMBO J. 18:188–197PubMedCrossRefGoogle Scholar
  48. 48.
    Holtmann H., Winzen R., Holland P., Eickemeier S., Hoffman E., Wallack D., Malinin N. L., Cooper J. A., Resch K., and Kracht M. et al., 1999, Induction of Interleukin-8 synthesis integrates effects on transcription and mRNA degradation from at least three different cytokine- or stress-activated signal transduction pathways. Mol. Cell Biol. 19:6742–6753PubMedGoogle Scholar
  49. 49.
    Shirin H., Sordillo E. M., Oh S. H., Yamamoto H., Delohery T., Weinstein I. B., and Moss S. F. et al, 1999, Helicobacter pylori inhibits the G1 to S transition in AGS gastric epithelial cells. Cancer Res. 59:2277–2281PubMedGoogle Scholar
  50. 50.
    Knipp U., Birkholz S., Kaup W., and Opferkuch W. et al., 1996, Partial characterization of a cell proliferation inhibiting protein produced by Helicobacter pylori. Infect. Immun. 64:3491–3496PubMedGoogle Scholar
  51. 51.
    Shenker B. J., and Datar S. et al., 1995, Fusobacterium nucleatum inihibits T cell activation by arresting cells in the mid Gl phase of the cell cycle. Infect. Immun. 63:4830–4836PubMedGoogle Scholar
  52. 52.
    Shirin H., Sordillo E. M., Delohery T., Weinstein I. B., and Moss S. F et al., 1999, Reduced expression of the cyclin-dependent kinase inhibitor, p27kipl in subclones of AGS gastric epithelial cells resistant to H. jfry/on-induced apoptosis. Gastroenterology 116:A503CrossRefGoogle Scholar
  53. 53.
    Lloyd R. V., Erikson L. A., Jin L., Kulig E., Qian X., Cheville J. C., and Scheithauer B. W. et al.,1999, p27kipl: A multifunctional cyclin-dependent kinase inhibitor with prognostic significance in human cancer. Am. J. Pathology 154:313–323CrossRefGoogle Scholar
  54. 54.
    Fero M. L., Randel E., Gurley K. E., Roberts J. M., and Kemp C. J. et al., 1998, The murine gene p27kipl is haplo-insufficient for tumour suppression. Nature 396:177–180PubMedCrossRefGoogle Scholar
  55. 55.
    Doig P., and Trust T. J. et al., 1997, The molecular basis for H. pylori adherence and colonization, in: The Immunobiology of H. pylori: From Pathogenesis to Prevention, PB Ernst, P Michetti, PD Smith, eds., Lippincott-Raven, PhiladelphiaGoogle Scholar
  56. 56.
    Ilver D., Arnqvist A., Ogren J., Frick I.-M., Kersulyte D., Incecik E. T, Berg D. E., Covacci A., Engstrand L., and Borens T. et al., 1998, Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by re tagging. Science 279:373–377PubMedCrossRefGoogle Scholar
  57. 57.
    Ishida M., Gomyo Y., Ttaebe S., Ohfuji S., and Ito H. et al., 1996, Apoptosis in human gastric mucosa, chronic gastritis, dysplasia and carcinoma: analysis by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling. Virchows. Arch. 428:229–235PubMedCrossRefGoogle Scholar
  58. 58.
    Moss S. F., Valle J., Abdalla A. M., Wang S., Siurala M., and Sipponen P. et al., 1999, Gastric cellular turnover and the development of atrophy after 31 years of follow up: a case-control study. Am. J. Gastroenterology 94:2109–2114CrossRefGoogle Scholar
  59. 59.
    Yabuki N., Sasano H., Tobita M., Imatani A., Hoshi T., Kato K., Ohara S., Asaki S., Toyota T., and Nagura H. et al., 1997, Analysis of cell damage and proliferation in Helicobacterpylori-mkcted human gastric mucosa from patients with gastric adenocarcinoma. Am. J. Pathol. 151:821–829PubMedGoogle Scholar
  60. 60.
    Lauwers G. Y., Scott G. V., and Karpeh M. S. et al., 1995, Immunohistochemical evaluation of bcl-2 protein expression in gastric adenocarcinomas. Cancer 75:2209–2213PubMedCrossRefGoogle Scholar
  61. 61.
    Kondo Shinomura Y., Kanayama S., Higashimoto Y., Miyagawa J. L., Minami T., Kiyohara T., Zushi S., Kitamura S., Isozaki K., and Matsuzawa Y. et al., 1996, Over-expression of Bcl-XL gene in human gastric adenomas and carcinomas. Int. J. Cancer 68:727–730CrossRefGoogle Scholar
  62. 62.
    Krajewska M., Fenoglio-Preiser C. M., Song K., Macdonald J. S., Stemmerman G., and Reed J. C. et al., 1996, Immunohistochemical analysis of the Bcl-2 family proteins in adenocarcinoma of the stomach. Am. J. Pathol. 149:1449–1457PubMedGoogle Scholar
  63. 63.
    Lu G.-D., Altieri D. C., and Tanigawa N. et al., 1998, Expression of a novel antiapoptosis gene, survivin, correlated with tumor cell apoptosis and p53 accumulation in gastric carcinomas. Cancer Res. 58:1808–1812Google Scholar
  64. 64.
    Bennett M. W., O’Connell J., O’SuUivan G. C., Roche D., Brady C., Kelly J., Collins J. K., and Shanahan F. et al., 1999, Expression of Fas ligand by human gastric adenocarcinomas: a potential mechanism of immune escape in stomach cancer. Gut. 44:156–162PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Emilia Mia Sordillo
    • 1
    • 2
  • Steven F. Moss
    • 2
  1. 1.Department of Pathology & Laboratory Medicine USA
  2. 2.Department of MedicineSt. Luke’s-Roosevelt Hospital Center/Columbia University New YorkUSA

Personalised recommendations