Helicobacter pylori-Induced Oxidative Stress and Inflammation

  • Hyeyoung KimEmail author
  • Young-Joon Surh
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)


Reactive oxygen species (ROS) are considered to be the important regulator in the pathogenesis of Helicobacter pylori-induced gastric ulceration and carcinogenesis. The sources of ROS are thought to be activated NADPH oxidase and CagA in H. pylori-infected gastric epithelial cells. Redox-sensitive transcription factors, nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), are the master regulators of inducible genes such as interleukin-8, monocyte chemoattractant protein-1, inducible nitric oxide synthase and cyclooxygenase-2, which are involved in gastric inflammation. Therefore, scavenging of ROS or specific inhibition of NF-κB and AP-1 may be an effective strategy for prevention or treatment of gastric inflammation associated with H. pylori infection. Proteinase-activated receptor 2(PAR2), which is activated by trypsin, is known to regulate expression of adhesion molecule integrins. H. pylori induces the expressions of PAR2 and integrin α5 and β1 as well as cell adhesion to fibronectin. H. pylori increases mRNA expression of trypsinogen 1 and 2 as well as the level and the activity of trypsin in gastric epithelial cells. H. pylori-induced production of ROS may mediate PAR2-mediated expression of integrins in gastric epithelial cells. Therefore, PAR2 may have an important role in gastric cell adhesion and possibly carcinogenesis associated with H. pylori infection. The genetic differences of H. pylori isolates, particularly in H. pylori virulence-associated genes, cag A, vac A and ice A genes, may influence the differential expression of inflammatory genes and clinical outcome of the infection. In this chapter we will discuss oxidative stress and inflammation in gastric mucosa caused by H. pylori infection in the context of roles of ROS, transcription factors, signaling mediators, proinflammatory molecules and PAR2. Animal models used for studying H. pylori-induced gastritis and gastric cancer are also described.


Activator protein-1 Apoptosis Chemokine Cyclooxygenase-2 Extracellular matrix Gastric epithelial cells Helicobacter pylori Inducible nitric oxide synthase Integrin Mitogen-activated protein kinase Nuclear factor-κB Proteinase-activated receptor 2 Toll-like receptor 



This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-002916) and a grant (Joint Research Project under the Korea–Japan Basic Scientific Cooperation Program) from NRF (F01-2009-000-10101-0). H. Kim is grateful to the Brain Korea 21 Project, college of Human Ecology, Yonsei University.


  1. 1.
    Marshall, B.J. (1994) Helicobacter pylori Am J Gastroenterol 89, S116–28.Google Scholar
  2. 2.
    Yoshida, N., Granger, D. N., Evans, D. J. Jr, Evans D. J., Graham D. Y., Anderson D. C., Wolf R. E., and Kvietys, P. R. (1993) Mechanisms involved in Helicobacter pylori-induced inflammation Gastroenterology 105, 1431–40.Google Scholar
  3. 3.
    Blaser, M. J. (1992) Hypothesis on the pathogenesis and natural history of Helicobacter pylori-induced inflammation Gastroenterology 102, 720  –7.Google Scholar
  4. 4.
    Nathan, C. F., Silverstein, S. C., Brukner, L. H., and Cohn, Z. A. (1979) Extracellular cytolysis by activated macrophages and granulocytes. II. Hydrogen peroxide as a mediator of cytotoxicity J Exp Med 149, 100–13.Google Scholar
  5. 5.
    Babior, B. M. (1984) Oxidants from phagocytes: agents of defense and destruction Blood 64, 959–66.Google Scholar
  6. 6.
    Weiss, S. J., and Lobuglio, A. F. (1982) Phagocyte-generated oxygen metabolites and cellular injury Lab Invest 47, 5–18.Google Scholar
  7. 7.
    Evans, D. J., Evans, D. G., Takemura, T., Nakano, H., Lampert, H. C., Graham D. Y., Granger, D. N., and Kvietys, P. R. (1995) Characterization of a Helicobacter pylori neutrophil activating protein Infect Immun 63, 2213–20.Google Scholar
  8. 8.
    Babior, B. M., Lambeth, J. D., and Nauseef, W. (2002) The neutrophil NADPH oxidase Arch Biochem Biophys 397, 342–4.CrossRefGoogle Scholar
  9. 9.
    Lambeth, J. D. (2002) Nox/Duox family of nicotinamide adenine dinucleotide (phosphate) oxidases Curr Opin Hematol 9, 11–7.Google Scholar
  10. 10.
    Lambeth, J. D. (2004) Nox enzyme and the biology of reactive oxygen Nat Rev Immunol 4, 181–9.CrossRefGoogle Scholar
  11. 11.
    Diekmann, D., Abo, A., Johnston, C., Segal, A. W., and Hall, A. (1994) Interaction of Rac with p67phox and regulation of phagocytic NADPH oxidase activity Science 265, 531–3.Google Scholar
  12. 12.
    Dorseuil, O., Quinn, M. T., and Bokoch, G. M. (1995) Dissociation of Rac translocation from p47phox /p67phox movements in human neutrophils by tyrosine kinase inhibitors J Leukoc Biol 58, 108–13.Google Scholar
  13. 13.
    Koga, H., Terasawa, H., Nunoi, H., Takeshige, K., Inagaki, F., and Sumimoto, H. (1999) Tetratricopeptide repeat (TPR) motifs of p67phox participate in interaction with the small GTPase Rac and activation of the phagocyte NADPH oxidase J Biol Chem 274, 25051–60.Google Scholar
  14. 14.
    Abo, A., Pick, E., Hall, A., Totty, N., Teahan, C. G., and Segal, A. W. (1991) Activation of the NADPH oxidase involves the small GTP-binding protein p21rac1 Nature 353, 668–70.Google Scholar
  15. 15.
    Diebold, B. A., and Bokoch, G. M. (2001) Molecular basis for Rac2 regulation of phagocyte NADPH oxidase Nat Immun 2, 211–15.Google Scholar
  16. 16.
    Mizuno, T., Kaibuchi, K., Ando, S., Musha, T., Hiraoka, K., Takaishi, K., Asada, M., Nunoi, H., Matsuda, I., and Takai, Y. (1992) Regulation of the superoxide-generating NADPH oxidase by a small GTP-binding protein and its stimulatory and inhibitory GDP/GTP exchange proteins J Biol Chem 267, 10215–18.Google Scholar
  17. 17.
    Kim, H., Seo, J. Y., and Kim, K. H. (1999) Effects of mannitol and dimethylthiourea on Helicobacter pylori-induced IL-8 production in gastric epithelial cells Pharmacology 59, 201–11.Google Scholar
  18. 18.
    Kim, H., Seo, J. Y., and Kim, K. H. (2000) Inhibition of lipid peroxidation, NF-κB activation and IL-8 production by rebamipide in Helicobacter pylori-stimulated gastric epithelial cells Dig Dis Sci 45, 621–8.Google Scholar
  19. 19.
    Rokutan, K., Kawahara, T., Kuwano, Y., Tominaga, K., Sekiyama, A., and Teshima-Kondo, S. (2006) NADPH oxidases in the gastrointestinal tract: A potential role of Nox 1 in innate immune response and carcinogenesis Antioxidants & Redox Signaling 8, 1573– 82.Google Scholar
  20. 20.
    Handa, O., Naito, Y., and Yoshikawa, T. (2007) CagA protein of Helicobacter pylori: A hijacker of gastric epithelial cell signaling Biochem Pharmacol 73, 1697–1702.Google Scholar
  21. 21.
    Zhang, Q. B., Nakashabendi, I. M., Mokhashi, M. S., Dawodu, J. B., Gemmell, C. G., and Russell, R. I. (1996) Association of cytotoxin production and neutrophil activation by strains of Helicobacter pylori isolated from patients with peptic ulceration and chronic gastritis Gut 38, 841–5.Google Scholar
  22. 22.
    Wei, Y. H., Lu, C. Y., Lee, H. C., Pang, C. Y., and Ma, Y. S. (1998) Oxidative damage and mutation to mitochondrial DNA and age-dependent decline of mitochondrial respiratory function Ann NY Acad Sci 854, 155–70.Google Scholar
  23. 23.
    Meyer-ter-Vehn, T., Covacci, A., Kist, M., and Pahl, H. L. (2000) Helicobacter pylori activates mitogen-activated protein kinase cascade and induces expression of the proto-oncogene c-fos and c-jun J Biol Chem 275, 16064–72.Google Scholar
  24. 24.
    Siebenlist, U., Franzoso, G., and Brown, K. (1994) Structure, regulation and function of NF-κB. Annu Rev Cell Biol 10, 405–55.PubMedCrossRefGoogle Scholar
  25. 25.
    Thanos, D., and Maniatis, T. (1995) NF-kappa B: a lesion in family values Cell 80, 529-32.Google Scholar
  26. 26.
    Lim, J. W., Kim, H., and Kim, K. H. (2001) NF-κB, inducible nitric oxide synthase and apoptosis by Helicobacter pylori infection Free Rad Biol Med 31, 355  –  66.Google Scholar
  27. 27.
    Keates, S., Hitti, Y. S., Upton, M., and Kelly, C. P. (1997) Helicobacter pylori infection activates NF-κB in gastric epithelial cells Gastroenterology 113, 1009  –99.Google Scholar
  28. 28.
    Mori, K., Ueda, A., Geleziunas, R., Wada, A., Hirayama, T., Yoshimura, T., and Yamamoto, N. (2001) Induction of monocyte chemoattractant protein1 by Helicobacter pylori involves NF-κB Infec Immune 69, 1280  –  6.Google Scholar
  29. 29.
    Brami-Cherrier, K., Roze, E., Girault, J-A., Betuing, S., and Caboche, J. (2009) Role of the ERK/MSK1 signaling pathway in chromatin remodelling and brain responses to drugs of abuse J Neurochem 108, 1323–35.Google Scholar
  30. 30.
    Brown, K., Gersberger, S., Carlson, L., Franzoso, G., and Siebenlist, U. (1995) Control of IκBα proteolysis by site-specific, signal-induced phosphorylation Science 267, 1485–8.Google Scholar
  31. 31.
    Sun, S. C., Ganchi, P. A., Beraud, C., Ballard, D. W., and Greene, W. C. (1994) Autoregulation of the NF-κB transactivator Rel A (p65) by multiple cytoplasmic inhibitors containing ankyrin motifs Proc Natl Acad Sci USA 91, 1346–50.Google Scholar
  32. 32.
    Wang, C.Y., Mayo, M. W., and Baldwin, A. S. Jr (1996) TNF-α and cancer therapy-induced apoptosis: potentiation by inhibition of NF-κB Science 274, 784–7.Google Scholar
  33. 33.
    Seo, J. H., Lim, J. W., Kim, H., and Kim, K. H. (2004) Helicobacter pylori in a Korean isolate activates mitogen-activated protein kinases, AP-1, and NF-kB and induces chemokine expression in gastric epithelial AGS cells Lab Invest 84, 49–62.Google Scholar
  34. 34.
    Angel, P., and Karin, M. (1991) The role of Jun, Fos and the AP-1 complex in cell proliferation and transformation Biochem Biophys Acta 1072, 129–39.Google Scholar
  35. 35.
    Treisman, R. (1996) Regulation of transcription by MAP kinase cascades Curr Opin Cell Biol 8, 205–15.CrossRefGoogle Scholar
  36. 36.
    Schenk, H., Klein, M., Erdbrugger, W., Droge, W., and Schulze-Osthoff, K. (1994) Distinct effects of thioredoxin and antioxidants on the activation of transcription factors NF-κB and AP-1 Proc Natl Acad Sci USA 91, 1672–6.Google Scholar
  37. 37.
    Aihara, M., Tsuchimoto, D., Takizawa, H., Azuma, A., Wakene, H., Ohmoto, Y., Imagawa, K., Kikuchi, M., Mukaida, N., and Matsuhsima, K. (1997) Mechanisms involved in Helicobacter pylori-induced interleukin-8 production by a gastric cancer cell line, MKN45 Infec Immun 65, 3218–24.Google Scholar
  38. 38.
    Masamune, A., Shimosegawa, T., Masamune, O., Mukaida, N., Koizumi, M., and Toyota, T. (1999) Helicobacter pylori-dependent ceramide production may mediate increased interleukin 8 expression in human gastric cancer cell lines Gastroenterology 116, 1330–41.Google Scholar
  39. 39.
    Chu, S. H., Kim, H., Seo, J. Y., Lim, J. W., Mukaida, N., and Kim, K. H. (2003) Role of NF-κB and AP-1 on Helicobacter pylori-induced IL-8 expression in AGS cells Dig Dis Sci 48, 257–65.Google Scholar
  40. 40.
    Seo, J. Y., Kim, H., and Kim, K. H. (2002) Transcriptional regulation by thiol compounds in Helicobacter pylori-induced interleukin-8 production in human gastric epithelial cells Ann N Y Acad Sci 973, 541–5.Google Scholar
  41. 41.
    Stein, B., Baldwin, A. S. Jr, Ballard, D. W., Greene, W. C., Angel, P., and Herrlich, P. (1993) Cross-coupling of the NF-κB p65 and Fos/Jun transcription factors produces potentiated biological function EMBO J 12, 3879–91.Google Scholar
  42. 42.
    Hsu, T. C., Young, M. R., Cmarik, J., and Colburn, N. H. (2000) Activator protein 1 and nuclear factor κB-dependent transcription events in carcinogenesis Free Rad Biol Med 28, 1338–48.Google Scholar
  43. 43.
    Li, J-J., Rhim, J. S., Schlegel, R., Vousden, K. H., and Colburn, N. H. (1998) Expression of dominant negative Jun inhibits elevated AP-1 and NF-κB transactivation and suppress anchorage independent growth of HPV immortalized human keratnocytes Oncogenes 16, 2711–21.Google Scholar
  44. 44.
    Whitmarsh, A. J. and Davis, R. J. (1996) Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways J Mol Med 74, 589–607.Google Scholar
  45. 45.
    Rinegaud, J., Whitmarsh, A. J., Barrett, T., Derjard, B., and Davis, R. J. (1996) MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway Mol Cell Biol 16, 1247–55.Google Scholar
  46. 46.
    Clerk, A., Kemp, T. J., Harrison, J. G., Mullen, A. J., Barton, P. j. R., and Sugden, P. H. (2002) Up-regulation of c-jun mRNA in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-Jun n-terminal kinases are required for efficient up-regulation of c-Jun protein Biochem J 368, 101–10.Google Scholar
  47. 47.
    Rossler, O. G., Steinmuller, L., Giehl, K. M., and Thiel, G. (2002) Role of c-Jun concentration in neuronal cell death J Neurosci Res 70, 655–64.Google Scholar
  48. 48.
    Han, T. H., and Prywes, R. (1995) Regulatory role of MEF2D in serum induction of the c-jun promoter Mol Cell Biol 15, 2907–15.Google Scholar
  49. 49.
    Naumann, M., Wessler, S., Bartsch, C., Wieland, B., Covacci, A., and Haas Meyer, T. F. (1999) Activation of activator protein-1 and stress response kinase in epithelial cells colonized by Helicobacter pylori encoding cag pathogenicity island J Biol Chem 274, 31655–62.Google Scholar
  50. 50.
    Garrington, T. P., and Johnson, G. L. (1999) Organization and regulation of mitogen-activated protein kinase signaling pathways Curr Opin Cell Biol 11, 211–8.CrossRefGoogle Scholar
  51. 51.
    Binetruy, B., Smeal, T., and Karin, M. (1991) Ha-Ras augments c-Jun activity and stimulates phosphorylation of its activation domain Nature (London) 351, 122–7.Google Scholar
  52. 52.
    Li, C., Hu, Y., Sturm, G., Wick, G., and Xu, Q. (2000) Ras/Rac-dependent activation of p38 mitogen-activated protein kinases in smooth muscle cells stimulated by cyclic strain stress. Arterioscler Thromb Vasc Bio 20:e1–e9.CrossRefGoogle Scholar
  53. 53.
    Keates, S., Sougioultzis, S., Keates, A. C., Zhao, D., Peek, R. M. Jr., Shaw, L. M., and Kelly, C. P. (2001) Cag+ Helicobacter pylori induce transactivation of the epidermal growth factor receptor in AGS gastric epithelialcells J Biol Chem 276, 48127–34.Google Scholar
  54. 54.
    Hirata, Y., Maeda, S., Mitsuno, Y., Tateishi, K., Yanai, A., Akanuma, M., Yoshida, H., Kawabe, T., Shiratori, Y., and Omata, M. (2002) Helicobacter pylori CagA protein activates serum response element-driven transcription independently of tyrosine phosphorylation Gasreoenterology 123, 1962–71.Google Scholar
  55. 55.
    Baggiolini, M., Loetscher, P., and Moser, B. (1995) Interleukin-8 and the chemokine family. Int J Immunopharmacol 17, 103–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Ben-Baruch, A., Michiel, D. F., and Oppenheim, J. J. (1995) Signals and receptors involved in recruitment of inflammatory cells. J Biol Chem 270, 11703–6.PubMedCrossRefGoogle Scholar
  57. 57.
    Fan, X. G., Chua, A., Fan, X. J., and Keeling, P. W. (1995) Increased gastric production of inlerleukin-8 of tumor necrosis factor in patients with Helicobacter pylori infection. J Clin Pathol 48, 133–  6.PubMedCrossRefGoogle Scholar
  58. 58.
    Ando, T., Kusugami, K., Ohsuga, M., Shinoda, M., Sakakibara, M., Saito, H., Fukatsu, A., Ichiyama, S., and Ohta, M. (1996) Interleukin-8 activity correlates with histological severity in Helicobacter pylori-associated antral gastritis Am J Gastroenterol 91, 1150  –  6.Google Scholar
  59. 59.
    Watanabe, N., Shimada, T., Ohtsuka, Y., Hiraishi, H., and Terano, A. (1997) Proinflammatory cytokines and Helicobacter pylori stimulate CC-chemokine expression in gastric epithelial cells. J Physiol Pharmacol 48, 405–13.PubMedGoogle Scholar
  60. 60.
    Jung, H. C., Kim, J. M., Song, I. S., and Kim, C. Y. (1997) Helicobacter pylori induces an array of pro-inflammatory cytokines in human gastric epithelial cells: quantification of mRNA for interleukin –8, -1 alpha/beta, granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant protein-1 and tumor necrosis factor-alpha J Gastroenerol Hepatol 12, 473–  80.Google Scholar
  61. 61.
    Shimoyama, T., Everett, S. M., Dixon, M. F., Axon, A. T., and Crabtree, J. E. (1998) Chemokine mRNA expression in gastric mucosa is associated with Helicobacter pylori cagA positivity and severity of gastritis J Clin Pathol 51, 765–70.Google Scholar
  62. 62.
    Roebuck, K. A. (1999) Oxidant stress regulation of IL-8 and ICAM-1 gene expression: differential activation and binding of the transcription factors AP-1 and NF-κB. Int J Mol Med 4. 223–230.PubMedGoogle Scholar
  63. 63.
    Muller, J. M., Rupec, R. A., and Baeuerle, P. A. (1997) Study of gene regulation by NF-κB and AP-1 in response to reactive oxygen intermediates. Methods 11, 301–12.PubMedCrossRefGoogle Scholar
  64. 64.
    O’Neil, G., and Hutchinson, A. F. (1993) Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Letters 330, 156  –160.Google Scholar
  65. 65.
    Williams, C. W., and DuBois, R. N. (1996) Prostaglandin endoperoxide synthase: why two isoforms? Am J Physiol 270, G393–  G400.PubMedGoogle Scholar
  66. 66.
    Tatsuguchi, A., Sakamoto, C., Wadam, K., Akamatsu, T., Tsukui, T., Miyake, K., Futagami, S., Kishida, T., Fukuda, Y., Yamanaka, N., and Kobayashi, M. (2000) Localization of cyclooxygenase 1 and cyclooxygenase 2 in Helicobacter pylori related gastritis and gastric ulcer tissues in humans. Gut 46, 782  –9.PubMedCrossRefGoogle Scholar
  67. 67.
    McCarthy, C. J., Crofford, L. J., Greenson, J., and Scheiman, J. M. (1999) Cyclooxygenase-2 expression in gastric antral mucosa before and after eradication of Helicobacter pylori infection. Am J Gastroenterol 94, 1218–23.PubMedCrossRefGoogle Scholar
  68. 68.
    Seibert, K., Zhang, Y., and Leahy, K. (1994) Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Nat Aca Sci USA 91, 12013–7.CrossRefGoogle Scholar
  69. 69.
    Plummer, S. M., Hall, M., and Faux, S. P. (1995) Oxidation and genotoxicity of fecapentaene-12 are potentiated by prostaglandin H synthase. Carcinogenesis 16, 1023–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Boolbol, S. K., Dannenberg, A. J., Chadburn, A., Martucci, C., Guo, X. J., Ramonetti, J. T., Abreu-Goris, M., Newmark, H. L., Lipkin, M. L., DeCosse, J. J., and Bertagnolli, M. M. (1996) Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res 56, 2556–60.PubMedGoogle Scholar
  71. 71.
    Hudson, N., Balsitis, M., Fillipowicz, F., and Hawkey, C. J. (1993) Effect of Helicobacter pylori colonization on gastric mucosal eicosanoid synthesis in patients taking non-steroidal anti-inflammatory drugs. Gut 34, 748–51.PubMedCrossRefGoogle Scholar
  72. 72.
    Fu, S., Ramanujam, K. S., Wong, A., Fantry, G. T., Drachenberg, C. B., James, S. P., Meltzer, S. J., and Wilson, K. T. (1999) Increased expression and cellular localization of inducible nitric oxide synthase and cyclooxygenase 2 in Helicobacter pylori gastritis. Gastroenterology 116, 1319–29.PubMedCrossRefGoogle Scholar
  73. 73.
    Varanasi, R. V., Ramanujam, K. S., and Wilson, K. T. (1998) A soluble factor from Helicobacter pylori induces expression and activity of cyclooxygenase-2. Gastroenterology 114, A1107. (Abstr.)Google Scholar
  74. 74.
    Cho, S. O., Lim, J. W., Kim, K. H., and Kim, H. (2010) Involvement of Ras and AP-1 in Helicobacter pylori-induced expression of COX-2 and iNOS in gastric epithelial AGS cells. Dig Dis Sci 55, 988–96.Google Scholar
  75. 75.
    Takehara, H., Iwamoto, J., Mizokami, Y., Takahashi, K., Ootubo, T., Miura, S., Narasaka, T., Takeyama, H., Omata, T., Shimokobe, K., Ito, M., and Matsuoka, T. (2006) Involvement of cyclooxygenase-2-prostaglandin E2 pathway in interleukin-8 production in gastric cancer cells. Dig Dis Sci 51, 2188  –97.PubMedCrossRefGoogle Scholar
  76. 76.
    Chang, Y. J., Wu, M. S., Lin, J. T., and Chen, C. C. (2005) Helicobacter pylori-induced invasion and angiogenesis of gastric cells is mediated by cyclooxygenase-2 induction through TLR2/TLR9 and promoter regulation. Journal of Immunology 175, 8242–  8252.Google Scholar
  77. 77.
    Kim, J. M., Kim, J. S., Jung, H. C., Song, I. S., and Kim, C. Y. (2002) Up-regulation of inducible nitric oxide synthase and nitric oxide in Helicobacter pylori-infected human gastric epithelial cells: possible role of interferon-gamma in polarized nitric oxide secretion. Helicobacter 7, 116–28.PubMedCrossRefGoogle Scholar
  78. 78.
    Son, H. J., Rhee, J. C., Park, D. I., Kim, Y. H., Rhee, P. L., Koh, K. C., Paik, S. W., Choi, K. W., and Kim, J. J. (2001) Inducible nitric oxide synthase expression in gastroduodenal diseases infected with Helicobacter pylori. Helicobacter 6, 37–  43.PubMedCrossRefGoogle Scholar
  79. 79.
    Lechner, M., Rieder, J., and Tilg, H. (2006) Helicobacter pylori infection, iNOS, and gastric cancer: the impact of another possible link. J Surg Oncol 94, 226  –33.CrossRefGoogle Scholar
  80. 80.
    Rachmilewitz, D., Karmeli, F., Eliakim, R., Stalnikowicz, R., Ackerman, Z., Amir, G., and Stamler, J. S. (1994) Enhanced gastric nitric oxide synthase activity in duodenal ulcer patients. Gut 35, 1394  –7.PubMedCrossRefGoogle Scholar
  81. 81.
    Tsuji, S., Kawano, S., Tsujii, M., Takei, Y., Tanaka, M., Sawaoka, H., Nagano, K., Fusamoto, H., and Kamada, T. (1996) Helicobacter pylori extract stimulates inflammatory nitric oxide production. Cancer Letters 108, 195–200.PubMedCrossRefGoogle Scholar
  82. 82.
    Mannick, E. E., Bravo, L. E., Zarama, G., Realpe, J. L., Zhang, X. J., Ruiz, B., Fontham, E. T.,Mera, R., Miller, M. J., and Correa, P. (1996) Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants. Cancer Res 56, 3238  –3247.PubMedGoogle Scholar
  83. 83.
    McDaniel,M.L., Kwon, G., Hill, J.R., Marshall, C.A., and Corbett, J.A. (1996) Cytokines and nitric oxide in islet inflammation and diabetes. Proc Soc Exp Biol Med 211, 24  –32.PubMedGoogle Scholar
  84. 84.
    Sawa, T., and Ohshima, H. (2006) Nitrative DNA damage in inflammation and its possible role in carcinogenesis. Nitric Oxide 14, 91–100.PubMedCrossRefGoogle Scholar
  85. 85.
    Rieder, G., Hofmann, J. A., Hatz, R.A., Stolte, M., and Enders, G. A. (2003) Up-regulation of inducible nitric oxide synthase in Helicobacter pylori-associated gastritis may represent an increased risk factor to develop gastric carcinoma of the intestinal type. Int J Med Microbiol 293, 403–12.PubMedCrossRefGoogle Scholar
  86. 86.
    Lee, J. S., Kim, H. S., Hahm, K. B., Sohn, M. W., Yoo, M., Johnson, J. A., and Surh, Y. J. (2007) Inhibitory effects of 7-carboxy. methyloxy-3′,4′,5-trimethoxyflavone (DA-6034) on Helicobacter pylori-induced NF-kappa B activation and iNOS expression in AGS cells. Ann N Y Acad Sci 1095, 527–35.PubMedCrossRefGoogle Scholar
  87. 87.
    Chen,C. N., Hsieh, F. J., Cheng, Y. M., Chang, K. J., and Lee, P. H. (2006) Expression of inducible nitric oxide snthase and cyclooxygenase-2 in angiogenesis and clinical outcome of human gastric cancer. J Surg Oncol 94, 226  –233.PubMedCrossRefGoogle Scholar
  88. 88.
    Thompson, C. B. (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267, 1456–62.PubMedCrossRefGoogle Scholar
  89. 89.
    Fukuo,K., Hata, S., Suhara, T., Nakahashi, T., Shinto, Y., Tsujimoto, Y., Morimoto, S., and Ogihara, T. (1996) Nitric oxide induces upregulation of Fas and apoptosis in vascular smooth muscle. Hypertension 27, 823–6.PubMedCrossRefGoogle Scholar
  90. 90.
    Bonfoco, E., Krainc, D., Ankarcrona, M., Nicotera, P., Lipton, S. A. (1995) Apoptosis and necrosis: Two distinct events induced, respectively, by mild and intense insults with N-methyl -D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci USA 92, 7162–6.PubMedCrossRefGoogle Scholar
  91. 91.
    Wagner, S., Beil, W., Westermann, J., Logan, R.P., Bock, C. T., Trautwein, C., Bleck, J. S., and Manns, M. P. (1998) Regulation of gastric epithelial cell growth by Helicobacter pylori: Evidence for a major role of apoptosis. Gastroenterology 113, 1836–47.CrossRefGoogle Scholar
  92. 92.
    Moss, S. F., Calam, J., Agarwal, B., Wang, S., and Holt, P. R. (1996) Induction of gastric epithelial apoptosis by Helicobacter pylori. Gut 38, 498–50.PubMedCrossRefGoogle Scholar
  93. 93.
    Isomoto, H., Miyazaki, M., Mizuta, Y., Takeshima, F., Murase, K., Inoue, K., Yamasaki, K., Murata, I., Koji, T., and Kohno, S. (2000) Expression of nuclear factor-κB in Helicobacter pylori-infected gastric mucosa detected with southwestern histochemistry. Scand J Gastroenterol. 35:247–54.andGoogle Scholar
  94. 94.
    Chartrain, N. A., Geller, D. A., Koty, P. P., Sitrin, N. F., Nussler, A. K., Hoffman, E. P., Billiar, T. R., Hutchinson, N. I., and Mudgett, J. S. (1994) Molecular cloning, structure, and chromosomal localization of the human inducible nitric oxide synthase gene. J Biol Chem 269, 6765–72.PubMedGoogle Scholar
  95. 95.
    Lindahl, T., and Andersson, A. (1972) Rate of chain breakage at apurinic sites in double-stranded deoxyribonucleic acid. Biochemistry 11, 3618–23.PubMedCrossRefGoogle Scholar
  96. 96.
    Fehsel, K., Kroncke, K. D., Meyer, K. L., Huber, H., Wahn, V., and Kolb, B.V. (1995) Nitric oxide induces apoptosis in mouse thymocytes. J Immunol 155, 2858–2865.PubMedGoogle Scholar
  97. 97.
    Mahr, S., Neumayer, N., Gerhard, M., Classen, M., and Prinz, C. (2000) IL-1β-induced apoptosis in rat gastric enterochromaffin-like cells is mediated by iNOS, NF-κB, and Bax protein. Gastroenterology 118, 515–24.PubMedCrossRefGoogle Scholar
  98. 98.
    Wu,H., and Lozano, G. (1994) NF-κB activation of p53. A potential mechanism for suppressing cell growth in response to stress. J Biol Chem 269, 20067–74.Google Scholar
  99. 99.
    Bash, J., Zong, W.X., and Gelinas, C. (1997) c-Rel arrests the proliferation of HeLa cells and affects critical regulators of the G1/S-phase transition. Mol Cell Biol 17, 6526  –36.PubMedGoogle Scholar
  100. 100.
    Grilli, M., Pizzi, M., Memo, M., and Spano, P. (1996) Neuroprotection by aspirin and sodium salycylate through blockade of NF-kB activation. Science 274, 1383–5.PubMedCrossRefGoogle Scholar
  101. 101.
    Kitajima, I., Nakajima, T., Imamura, T., Takasaki, I., Kawahara, K., Okano, T., Tokioka, T., Soejima, Y., Abeyama, K., and Maruyama, I. (1996) Induction of apoptosis in murine clonal osteoblasts expressed by human T-cell leukemia virus type I tax by NF-κB and TNF-α. J Bone Miner Res 11, 200  –10.PubMedCrossRefGoogle Scholar
  102. 102.
    Bessho, R, Matsubara K, Kubota M, Kuwakado K, Hirota H, Wakazono Y, et al. (1994) Pyrrolidine dithiocarbamate, a potent inhibitor of nuclear factor κB (NF-κB) activation, prevents apoptosis in human promyelocytic leukemia HL-60 cells and thymocytes. Biochem Pharmacol 48, 1883–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Wang, C. Y,, Mayo, M. W, and Baldwin, A. S. Jr. (1996) TNF-α and cancer therapy-induced apoptosis: potentiation by inhibition of NF-κB. Science 274, 784–7.PubMedCrossRefGoogle Scholar
  104. 104.
    Van Antwerp, D. J., Martin, S. J., Kafri T., Green, D. R., and Verma, I. M. (1996) Suppression of TNF-α-induced apoptosis by NF--κB. Science 274, 787–9.PubMedCrossRefGoogle Scholar
  105. 105.
    Nystedt, S., Emilsson, K., Wahlestedt, C., and Sundelin, J. (1994) Molecular cloning of a potential proteinase activated receptor Proc Natl Acad Sci USA 91, 9208–12.CrossRefGoogle Scholar
  106. 106.
    Coughlin, S. R, Camerer, E. (2003) PARticipation in inflammation. J Clin Invest 111, 25–7.PubMedGoogle Scholar
  107. 107.
    Hou, L., Kapas, S., Cruchley, A. T., Macey, M. G., Harriott, P., Chinni, C., Stone, S. R., and Howells, G. L. (1998) Immunolocalization of protease-activated receptor-2 in skin: receptor activation stimulates interleukin-8 secretion by keratinocytes in vitro. Immunology 94, 356–62.PubMedCrossRefGoogle Scholar
  108. 108.
    Mosmann, T. (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65, 55–63.PubMedCrossRefGoogle Scholar
  109. 109.
    Vergnolle, N. (1999) Proteinase-activated receptor-2-activating peptides induce leukocyte rolling, adhesion, and extravasation in vivo. J Immunol 163, 5064  –9.PubMedGoogle Scholar
  110. 110.
    Belham, C. M., Tate, R. J., Scott, P. H., Pemberton, A. D., Miller, H. R., Wadsworth, R. M., Gould, G. W., and Plevin, R. (1996) Trypsin stimulates proteinase-activated receptor-2-dependent and -independent activation of mitogen-activated protein kinases Biochem J 320, 939–46.Google Scholar
  111. 111.
    Mirza, H., Yatsula, V., and Bahou, W. F. (1996) The proteinase activated receptor-2 (PAR-2) mediates mitogenic responses in human vascular endothelial cells J Clin Invest 97, 1705–14.Google Scholar
  112. 112.
    Syeda, F., Grosjean, J., Houliston, R. A., Keogh, R. J., Carter, T. D., Paleolog, E., and Wheeler-Jones, C. P. (2006) Cyclooxygenase-2 induction and prostacyclin release by protease-activated receptors in endothelial cells require cooperation between mitogen-activated protein kinase and NF-kappaB pathways J Biol Chem 281, 11792–  804.Google Scholar
  113. 113.
    Fujimoto, D., Hirono, Y., Goi, T., Katayama, K., Hirose, K., and Ymaguchi, A. (2006) Expression of protease activated receptor-2 (PAR-2) in gastric cancer J Surg Oncol 93, 139–44.Google Scholar
  114. 114.
    Kajikawa, H., Yoshida, N., Katada, K., Hirayama, F., Handa, O., Kokura, S., Naito, Y., and Yoshikaw, T. (2007) Helicobacter pylori activates gastric epithelial cells to produce interleukin -8 via protease-activated receptor 2 Digestion 76, 248–55.Google Scholar
  115. 115.
    Olbe, L. (2007) Strong activation of PAR-2 receptors: A common trigger for the development of gastrointestinal adenocarcinoma Scandinavian J Gastroenterol 42, 1133–7.Google Scholar
  116. 116.
    Kamath, L., Meydani, A., Foss, F., and Kuliopulos, A. (2001) Signaling from protease-activated receptor-1 inhibits migration and invasion of breast cancer cells Cancer Res 61, 5933–40.Google Scholar
  117. 117.
    Koshikawa, N., Hasegawa, S., Nagashima, Y., Mitsuhashi, K., Tsubota, Y., Miyata, S., Miyagi, Y., Yasumitsu, H., and Miyazaki, K. (1998) Expression of trypsin by epithelial cells of various tissues, leukocytes, and neurons in human and mouse Am J Pathol 153, 937–44.Google Scholar
  118. 118.
    Koshikawa, N., Nagashima, Y., Miyagi, Y., Mizushima, H., Yanoma, S., Yasumitsu, H., and Miyazaki, K. (1997) Expression of trypsin in vascular endothelial cells FEBS Lett 409, 442–8.Google Scholar
  119. 119.
    Koivunen, E., Saksela, O., Itkonen, O., Osman, S., Huhtala, M. L., and Stenman, U. H. (1991) Human colon carcinoma, fibrosarcoma and leukemia cell lines produce tumor-associated trypsinogen Int J Cancer 47, 592–596.Google Scholar
  120. 120.
    Walz, D. A., Fenton, J. W. (1994) The role of thrombin in tumor cell metastasis Invasion Metastasis 14, 303–308.Google Scholar
  121. 121.
    Seo, J. H., Lim, J. W., Yoon, J. H., and Kim, H. (2009) Protease-activated receptor-2 mediates the expression of integrin alpha 5 and beta 1 in Helicobacter pylori-infected gastric epithelial AGS cells Digestion 80, 40–9.Google Scholar
  122. 122.
    Ohta, T., Tajima, H., Fushida, S., Kitagawa, H., Kayahara, M., Nagakawa, T., Miwa, K., Yamamoto, M., Numata, M., Nakanuma, Y., Kitamura, Y., and Terada, T. (1998) Cationic trypsinogen produced by human pancreatic ductal cancer has the characteristics of spontaneous activation and gelatinolytic activity in the presence of proton Int J Mol Med 1, 689–92.Google Scholar
  123. 123.
    Miyata, S., Koshikawa, N., Miyata, S., Koshikawa, N., Yasumitsu, H., and Miyazaki, K. (2000) Trypsin stimulates integrin α5β1-dependent adhesion to fibronectin and proliferation of human gastric carcinoma cells through activation of proteinase-activated receptor-2 J Biol Chem 275, 4592–8.Google Scholar
  124. 124.
    Yahagi, N., Ichinose, M., Matsushima, M., Matsubara, Y., Miki, K., and Kurokawa, K. (1996) Complementary DNA cloning and sequencing of rat enterokinase and tissue distribution of its mRNA Biochem Biophys Res Commun 219, 806–12.Google Scholar
  125. 125.
    Miyata, S., Koshikawa, N., Yasumitsu, H., and Miyazaki, K. (2000) Trypsin stimulates integrin alpha(5)beta(1)-dependent adhesion to fibronectin and proliferation of human gastric carcinoma cells through activation of proteinase-activated receptor-2 J Biol Chem 275, 4592–8.Google Scholar
  126. 126.
    Banfi, C., Brioschi, M., Barbieri, S. S., Eligini, S., Barcella, S., Tremoli, E., Colli, S., and Mussoni, L. (2009) Mitochondrial reactive oxygen species: a common pathway for PAR1- and PAR2-mediated tissue factor induction in human endothelial cells J Thromb Haemost 7, 206–16.Google Scholar
  127. 127.
    Seo, J. H., Kim, K. H., and Kim, H. (2007) Role of proteinase-activated receptor-2 on cyclooxygenase-2 expression in H. pylori-infected gastric epithelial cells Ann N Y Acad Sci 1096, 29–36.PubMedCrossRefGoogle Scholar
  128. 128.
    Lim, S. Y., Tennant, G. M., Kennedy, S., Wainwright, C. L., Kane, K. A. (2006) Activation of mouse protease-activated receptor-2 induces lymphocyte adhesion and generation of reactive oxygen species Br. J Pharmacol 149, 591–9.Google Scholar
  129. 129.
    Hynes, R. O. (1992) Integrins: versatility, modulation, and signaling in cell adhesion Cell 69, 11–25.Google Scholar
  130. 130.
    Watt, F. M. (1994) Studies with cultured human epidermal keratinocytes: potential relevance to corneal wound healing Eye 8, 161–2.Google Scholar
  131. 131.
    Zambruno, G., Marchisio, P. C., Marconi, A., Vaschieri, C., Melchiori, A., Giannetti, A., and De Luca, M. (1995) Transforming growth factor-beta 1 modulates beta 1 and beta 5 integrin receptors and induces the de novo expression of the alpha v beta 6 heterodimer in normal human keratinocytes: implications for wound healing J Cell Biol 129, 853–865.Google Scholar
  132. 132.
    Liotta, L. A., Rao, C. N., and Wewer, U. M. (1986) Biochemical interactions of tumor cells with the basement membrane Annu Rev Biochem 55, 1037–1057.Google Scholar
  133. 133.
    Lim, J. W., Kim, H., Kim, K. H. (2003) Cell adhesion-related gene expression by Helicobacter pylori in gastric epithelial AGS cells Int J Biochem Cell Biol 35, 1284–1296.Google Scholar
  134. 134.
    Giancotti, F. G., Mainiero, F. (1994) Integrin-mediated adhesion and signaling in tumorigenesis Biochim Biophys Acta 1198, 47–64.Google Scholar
  135. 135.
    Ura, H., Denno, R., Hirata, K., Yamaguchi, K., and Yasoshima, T. (1998) Separate functions of alpha2beta1 and alpha3beta1 integrins in the metastatic process of human gastric carcinoma Surg Today 28, 1001–1006.Google Scholar
  136. 136.
    Cox, J. M., Clayton, C. L., Tomita, T., Wallace, D. M., Robinson, P. A., and Crabtree, J. E. (2001) Susceptibility of lipopolysaccharide mutants to the bactericidal action of human neutrophil lysosomal fractions Infect Immun 69, 6970–6980.Google Scholar
  137. 137.
    Sepulveda, A. R., Tao, H., Carloni, E., Sepulveda, J., Graham, D. Y., and Peterson, L. E. (2002) Screening of gene expression profiles in gastric epithelial cells induced by Helicobacter pylori using microarray analysis Aliment Pharmacol Ther 16, 145–157.Google Scholar
  138. 138.
    Brass, L. F., Manning, D. R., Cichowski, K., and Abrams, C. S. (1997) Signaling through G proteins in platelets: to the integrins and beyond Thromb Haemost 78, 581–589.Google Scholar
  139. 139.
    Sadok, A., Pierres, A., Dahan, L., Prévôt, C., Lehmann, M., and Kovacic, H. (2009) NADPH oxidase 1 controls the persistence of directed cell migration by a Rho-dependent switch of alpha2/alpha3 integrins Mol Cell Biol 29, 2915–3928.Google Scholar
  140. 140.
    Ksiazek, K., Mikula-Pietrasik, J., Korybalska, K., Dworacki, G., Jörres, A., and Witowski, J. (2009) Senescent peritoneal mesothelial cells promote ovarian cancer cell adhesion: the role of oxidative stress-induced fibronectin Am J Pathol 174, 1230–1240.Google Scholar
  141. 141.
    Akopyants, N. S., Clifton, S. W., Kersulyte, D., Crabtree, J. E., Youree, B. E., Reece, C.A., Bukanor, N.O., Drazek, E.S., Roe, B.A., and Berg, D.E. (1998) Analyses of the cag ­pathogenicity island of Helicobacter pylori. Mol. Microbiol 28, 37–54.PubMedCrossRefGoogle Scholar
  142. 142.
    Keates, S., Keates, A. C., Warny, M., Peek, R. M. Jr., Murray, P. G. & Kelly, C. P. (1999) Differential activation of mitogen-activated protein kinases in AGS gastric epithelial cells by cag + and cag - Helicobacter pylori. J Immunol 163, 5552–9.PubMedGoogle Scholar
  143. 143.
    Kuipers, E. J., Perez-Perez, G. I., Meuwissen, S. G., & Blaser, M. J. (1995) Helicobacter pylori and atrophic gastritis: importance of the cagA status J Natl Cancer Inst 87, 1777–80.CrossRefGoogle Scholar
  144. 144.
    Mobley, H. L. (1997) Defining Helicobacter pylori as a pathogen: strain heterogenicity and virulence Am J Med 100, 2S–11S.Google Scholar
  145. 145.
    Atherton, J. C., Peek, R. M. J., Tham, K. T., Cover, T. L., and Blaser, M. J. (1997) Clinical and pathological importance of heterogenicity on vacA, the vacuolating cytotoxin gene of Helicobacter pylori. Gastroenterology 112, 92–9.PubMedCrossRefGoogle Scholar
  146. 146.
    Van Doorn, L. J., Figueiredo, C., Sanna, R., Pena, A. S., Midolo, P., Ng, E. K., Atherton, J. C., Blaser, M. J., and Quint, W., G. (1998) Expanding allelic diversity of Helicobacter pylori vacA. J Clin Microbiol 36, 2597–  603.Google Scholar
  147. 147.
    Atherton, J. C., Cao, P., Peek. R., M. J., Tummuru, M. K., Blaser, M. J., and Cover, T. L. (1995) Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration J Biol Chem 270, 17771–7.Google Scholar
  148. 148.
    Peek, R. M. J., Thompson, S. A., Donahue, J. P., Tham, K.T., Atherton, J. C., Blaser, M. J., and Miller, G. G. (1998) Adherence to gastric epithelial cells induces expression of a Helicobacter pylori gene, iceA, that is associated with clinical outcome Proc Assoc Am Phys 110, 532–44.Google Scholar
  149. 149.
    Figueiredo, C., Van Doorn, L-J., Nogueira, C., Soares, J. M., Pinho, C., Figueira, P., Quint, W. G. V., and Carneiro, F. (2001) Helicobacter pylori genotypes are associated with clinical outcome in Portuguese patients and show a high prevalence of infections with multiple strains Scand J Gastroenterol 36, 128–35.Google Scholar
  150. 150.
    Yamaoka, Y., Kodama, T., Gutierrez, O., Kim, J. G., Kashima, K., & Graham, D. Y. (1999) Relationship between Helicobacter pylori iceA, cagA, and vacA status and clinical outcome: studies in four different countries J Clin Microbiol 37, 2274  –9.Google Scholar
  151. 151.
    Konturek, P. C., Konturek, S. J., and Brzozowski, T. (2006) Gastric cancer and Helicobacter pylori infection J Physiol Pharmacol Suppl 3, 51–65.Google Scholar
  152. 152.
    Konturek, P. C., Konturek, S. J., and Brzozowski, T. (1998) Animal models for host-pathogen interaction studies Br Med Bull 54, 163–73.Google Scholar
  153. 153.
    Kodama, M., Murakami, K., Sato, R., and Okimoto, T. (2005) Helicobacter pylori-infected animal models are extremely suitable for the investigation of gastric carcinogenesis World J Gastroenterol 11, 7063–71.Google Scholar
  154. 154.
    Jeremy, A. H., Du, Y., Dixon, M. F., Robinson, P. A., and Crabtree, J. E. (2006) Protection against Helicobacter pylori infection in the Mongolian gerbil after prophylactic vaccination Microbes Infect 8, 340–6.Google Scholar
  155. 155.
    Matsubara, S. (2004) Cloning of Mongolian gerbil cDNAs encoding inflammatory proteins, and their expression in glandular stomach during H. pylori infection Cancer Sci 95, 798–802.PubMedCrossRefGoogle Scholar
  156. 156.
    Koyama, M. J. (2000) Distribution of IκB proteins in gastric mucosa and other organs of mouse and gerbil Histochem Cytochem 48, 191–99.Google Scholar
  157. 157.
    Yanai, A., Maeda, S., Shibata, W., Hikiba, Y., Sakamoto, K., Nakagawa, H., Ohmae, T., Hirata, Y., Ogura, K., Muto, S., Itai, A., and Omata, M. (2008) Activation of IκB kinase and NF-κB is essential for Helicobacter pylori-induced chronic gastritis in Mongolian gerbils. Infect Immun 76, 781–7.PubMedCrossRefGoogle Scholar
  158. 158.
    Rogers, A. B., and Houghton J. (2009) Helicobacter-based mouse models of digestive system carcinogenesis Methods Mol Biol 511, 267–95.Google Scholar
  159. 159.
    Lee, A. (1995) Development of a mouse model of Helicobacter pylori infection that mimics human disease Ann Med 27, 575–82.Google Scholar
  160. 160.
    Marchetti, M., Aricò, B., Burroni, D., Figura, N., Rappuoli, R., and Ghiara, P. (1995) Development of a mouse model of Helicobacter pylori infection that mimics human disease Science 267, 1655–8.Google Scholar
  161. 161.
    Lee, A., O’Rourke, J., De Ungria, M. C., Robertson, B., Daskalopoulos, G., and Dixon, M. F. (1997) A standardized mouse model of Helicobacter pylori infection: introducing the Sydney strain J Gastroenterology 112, 1386–97.Google Scholar
  162. 162.
    van Doorn, N. E., van Rees, E. P., Namavar, F., Ghiara, P., Vandenbroucke-Grauls, C. M., and de Graaff, J. (1999) The inflammatory response in CD1 mice shortly after infection with a CagA+/VacA+ Helicobacter pylori strain Clin Exp Immunol 115, 421–7.PubMedCrossRefGoogle Scholar
  163. 163.
    Rabelo-Gonçalves, E. M., Nishimura, N. F., and Zeitune, J. M. (2005) Development of a BALB/c mouse model of Helicobacter pylori infection with fresh and frozen bacteria Biol Res 38, 101–9.Google Scholar
  164. 164.
    Nagata, J., Kijima, H., Takagi, A., Ito, M., Goto, K., Yamazaki, H., Nakamura, M., Mine, T., and Ueyama, Y. (2004) Helicobacter pylori induces chronic active gastritis in p53-knockout mice Int J Mol Med 13, 773–7.PubMedGoogle Scholar
  165. 165.
    Rokbi, B., Seguin, D., Guy, B., Mazarin, V., Vidor, E., Mion, F. Cadoz, M., and Quentin-Millet, M. J. (2001) Assessment of Helicobacter pylori gene expression within mouse and human gastric mucosae by real-time reverse transcriptase PCR Infect Immun 69, 4759–66.Google Scholar
  166. 166.
    Ferrer, R. L., Avé, P., Ndiaye, D., Bambou, J. C., Huerre, M. R., Philpott, D. J., and Mémet, S. (2008) NF-κB activation during acute Helicobacter pylori infection in mice Infect Immun 76, 551–61.Google Scholar
  167. 167.
    Oshima, H., Oguma, K., Du, Y. C., and Oshima, M. (2009) Prostaglandin E2, Wnt, and BMP in gastric tumor mouse models Cancer Sci 100, 1779–85.Google Scholar
  168. 168.
    Toller, I. M., Hitzler, I., Sayi, A., and Mueller, A. (2010) Prostaglandin E2 prevents Helicobacter-induced gastric preneoplasia and facilitates persistent infection in a mouse model Gastroenterology 138, 1455–67.PubMedCrossRefGoogle Scholar
  169. 169.
    Takasu, S., Tsukamoto, T., Cao, X. Y., Toyoda, T., Hirata, A., Ban, H., Yamamoto, M., Sakai, H., Yanai, T., Masegi, T., Oshima, M., and Tatematsu, M. (2008) Roles of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 expression and beta-catenin activation in gastric carcinogenesis in N-methyl-N-nitrosourea-treated K19-C2mE transgenic mice Cancer Sci 99, 2356–64.PubMedCrossRefGoogle Scholar
  170. 170.
    Chen, D., Stenström, B., Zhao, C. M., and Wadström, T. (2007) Does Helicobacter pylori infection per se cause gastric cancer or duodenal ulcer? Inadequate evidence in Mongolian gerbils and inbred mice FEMS Immunol Med Microbiol 50, 184–9.CrossRefGoogle Scholar
  171. 171.
    Kim, D. H., Kim, S. W., Song, Y. J., Oh, T. Y., Han, S. U., Kim, Y. B., Joo, H. J., Cho, Y. K., Kim, D.Y., Cho, S. W., Kim, M. W., Kim, J. H., and Hahm, K. B. (2003) Long-term evaluation of mice model infected with Helicobacter pylori: focus on gastric pathology including gastric cancer Aliment Pharmacol Ther 18 Suppl 1, 14–23.Google Scholar
  172. 172.
    Han, S. U., Kim, Y. B., Joo, H. J., Hahm, K. B., Lee, W. H., Cho, Y. K., Kim, D. Y., and Kim, M. W. (2002) Helicobacter pylori infection promotes gastric carcinogenesis in a mice model J Gastroenterol Hepatol 17, 253–61.Google Scholar
  173. 173.
    Shimizu, N., Kaminishi, M., Tatematsu, M., Tsuji, E., Yoshikawa, A., Yamaguchi, H., Aoki, F., and Oohara,T. (1998) Helicobacter pylori promotes development of pepsinogen-altered pyloric glands, a preneoplastic lesion of glandular stomach of BALB/c mice pretreated with N-methyl-N-nitrosourea Cancer Lett 123, 63–9.PubMedCrossRefGoogle Scholar
  174. 174.
    Fox, J. G., Dangler, C. A., Taylor, N. S., King, A., Koh, T. J., and Wang, T. C. (1999) High-salt diet induces gastric epithelial hyperplasia and parietal cell loss, and enhances Helicobacter pylori colonization in C57BL/6 mice Cancer Res 59, 4823–8.PubMedGoogle Scholar
  175. 175.
    Rogers, A. B., Taylor, N. S., Whary, M. T., Stefanich, E. D., Wang, T. C., and Fox, J. G. (2005) Helicobacter pylori but not high salt induces gastric intraepithelial neoplasia in B6129 mice Cancer Res 65, 10709–15.PubMedCrossRefGoogle Scholar
  176. 176.
    Touati, E., Michel, V., Thiberge, J. M., Wuscher, N., Huerre, M., and Labigne, A. (2003) Chronic Helicobacter pylori infections induce gastric mutations in mice Gastroenterology 124, 1408–19.Google Scholar
  177. 177.
    Konturek, S. J., Konturek, P. C., Konturek, J. W., Plonka, M., Czesnikiewicz-Guzik, M., Brzozowski, T., and Bielanski, W. (2006) Helicobacter pylori and its involvement in gastritis and peptic ulcer formation J Physiol Pharmacol 57, 29–50.Google Scholar
  178. 178.
    Rogers, A. B., and Houghton, J. (2009) Helicobacter-based mouse models of digestive system carcinogenesis. Methods Mol Biol 511, 267–95.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Food and Nutrition, Brain Korea 21 Project, College of Human EcologyYonsei UniversitySeoulSouth Korea

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