Seminars in Immunopathology

, Volume 30, Issue 3, pp 315–327 | Cite as

Nox enzymes and oxidative stress in the immunopathology of the gastrointestinal tract

  • Kazuhito RokutanEmail author
  • Tsukasa Kawahara
  • Yuki Kuwano
  • Kumiko Tominaga
  • Keisei Nishida
  • Shigetada Teshima-Kondo


Chronic inflammation caused by Helicobacter pylori infection or inflammatory bowel disease (IBD) is closely linked to cancer development. Innate immune abnormalities and enhanced production of reactive oxygen species through a phagocyte NADPH oxidase (Nox2) are key issues in understanding the pathogenesis of inflammation-dependent carcinogenesis. Besides Nox2, functionally distinct homologues (Nox1, Nox3, Nox4, Nox5, Duox1, and Duox2) have been identified. Nox1 and Duox2 are highly expressed in the gastrointestinal tract. Although the functional roles of Nox/Duox in the gastrointestinal tract are still unclear, we will review their potential roles in the gastrointestinal immunopathology, particularly in H. pylori-induced inflammation, IBD, and malignancy.


Nox1 Nox2 Duox2 Innate immunity Inflammation Carcinogenesis 


  1. 1.
    Abreu MT, Fukata M, Arditi M (2005) TLR signaling in the gut in health and disease. J Immunol 174:4453–4460, MedlinePubMedGoogle Scholar
  2. 2.
    Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801PubMedGoogle Scholar
  3. 3.
    Allen L-AH (2000) Modulating phagocyte activation: the pros and cons of Helicobacter pylori virulence factors. J Exp Med 191:1451–1454, Medline DOI  10.1084/jem.191.9.1451 PubMedGoogle Scholar
  4. 4.
    Allen L-AH (2007) Phagocytosis and persistence of Helicobacter pylori. Cell Microbiol 9:817–828, Medline DOI  10.1111/j.1462-5822.2007.00906.x PubMedGoogle Scholar
  5. 5.
    Allen L-AH, Beecher BR, Lynch JT, Rohner OV, Wittine LM (2005) Helicobacter pylori disrupts NADPH oxidase targeting in human neutrophils to induce extracellular superoxide release. J Immunol 174:3658–3667, MedlinePubMedGoogle Scholar
  6. 6.
    Ambasta RK, Kumar P, Griendling KK, Schmidt HHHW, Busse R, Brandes RP (2004) Direct interaction of the novel Nox proteins with p22phox is required for the formation of a functionally active NADPH Oxidase. J Biol Chem 279:45935–45941, Medline DOI  10.1074/jbc.M406486200 PubMedGoogle Scholar
  7. 7.
    Ameziane-El-Hassani R, Morand S, Boucher J-L, Frapart Y-M, Apostolou D, Agnandji D, Gnidehou S, Ohayon R, Noel-Hudson M-S, Francon J, Lalaoui K, Virion A, Dupuy C (2005) Dual oxidase-2 has an intrinsic Ca2+ -dependent H2O2-generating activity. J Biol Chem 280:30046–30054, Medline DOI  10.1074/jbc.M500516200 PubMedGoogle Scholar
  8. 8.
    Amieva MR, El-Omar EM (2008) Host–bacterial interactions in Helicobacter pylori infection. Gastroenterology 134:306–323, Medline DOI  10.1053/j.gastro.2007.11.009 PubMedGoogle Scholar
  9. 9.
    Arbiser JL, Petros J, Klafter R, Govindajaran B, McLaughlin ER, Brown LF, Cohen C, Moses M, Kilroy S, Arnold RS, Lambeth JD (2002) Reactive oxygen generated by Nox1 triggers the angiogenic switch. PNAS 99:715–720, Medline DOI  10.1073/pnas.022630199 PubMedGoogle Scholar
  10. 10.
    Arnold RS, Shi J, Murad E, Whalen AM, Sun CQ, Polavarapu R, Parthasarathy S, Petros JA, Lambeth JD (2001) Hydrogen peroxide mediates the cell growth and transformation caused by the mitogenic oxidase Nox1. PNAS 98:5550–5555, Medline DOI  10.1073/pnas.101505898 PubMedGoogle Scholar
  11. 11.
    Aspholm-Hurtig M, Dailide G, Lahmann M, Kalia A, Ilver D, Roche N, Vikstrom S, Sjostrom R, Linden S, Backstrom A, Lundberg C, Arnqvist A, Mahdavi J, Nilsson UJ, Velapatino B, Gilman RH, Gerhard M, Alarcon T, Lopez-Brea M, Nakazawa T, Fox JG, Correa P, Dominguez-Bello MG, Perez-Perez GI, Blaser MJ, Normark S, Carlstedt I, Oscarson S, Teneberg S, Berg DE, Boren T (2004) Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin. Science 305:519–522, Medline DOI  10.1126/science.1098801 PubMedGoogle Scholar
  12. 12.
    Augusto AC, Miguel F, Mendonca S, Pedrazzoli Jr J, Gurgueira SA (2007) Oxidative stress expression status associated to Helicobacter pylori virulence in gastric diseases. Clin Biochem 40:615–622, Medline DOI  10.1016/j.clinbiochem.2007.03.014 PubMedGoogle Scholar
  13. 13.
    Baik S-C, Youn H-S, Chung M-H, Lee W-K, Cho M-J, Ko G-H, Park C-K, Kasai H, Rhee K-H (1996) Increased oxidative DNA damage in Helicobacter pylori-infected human gastric mucosa. Cancer Res 56:1279–1282, MedlinePubMedGoogle Scholar
  14. 14.
    Baillon M-LA, van Vliet AHM, Ketley JM, Constantinidou C, Penn CW (1999) An iron-regulated alkyl hydroperoxide reductase (AhpC) confers arotolerance and oxidative stress resistance to the microaerophilic pathogen Campylobacter jejuni. J Bacteriol 181:4798–4804, MedlinePubMedGoogle Scholar
  15. 15.
    Banfi B, Clark RA, Steger K, Krause K-H (2003) Two novel proteins activate superoxide generation by the NADPH oxidase NOX1. J Biol Chem 278:3510–3513, Medline DOI  10.1074/jbc.C200613200 PubMedGoogle Scholar
  16. 16.
    Banfi B, Maturana A, Jaconi S, Arnaudeau S, Laforge T, Sinha B, Ligeti E, Demaurex N, Krause K-H (2000) A mammalian H+ channel generated through alternative splicing of the NADPH oxidase homolog NOH-1. Science 287:138–142, Medline DOI  10.1126/science.287.5450.138 PubMedGoogle Scholar
  17. 17.
    Banfi B, Molnar G, Maturana A, Steger K, Hegedus B, Demaurex N, Krause K-H (2001) A Ca2+ -activated NADPH oxidase in testis, spleen, and lymph nodes. J Biol Chem 276:37594–37601, Medline DOI  10.1074/jbc.M103034200 PubMedGoogle Scholar
  18. 18.
    Bedard K, Krause K-H (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313, Medline DOI  10.1152/physrev.00044.2005 PubMedGoogle Scholar
  19. 19.
    Blaser MJ, Atherton JC (2004) Helicobacter pylori persistence: biology and disease. J Clin Invest 113:321–333, MedlinePubMedGoogle Scholar
  20. 20.
    Brewer AC, Sparks EC, Shah AM (2006) Transcriptional regulation of the NADPH oxidase isoform, Nox1, in colon epithelial cells: role of GATA-binding factor(s). Free Radic Biol Med 40:260–274, Medline DOI  10.1016/j.freeradbiomed.2005.08.022 PubMedGoogle Scholar
  21. 21.
    Brown JR, Goldblatt D, Buddle J, Morton L, Thrasher AJ (2003) Diminished production of anti-inflammatory mediators during neutrophil apoptosis and macrophage phagocytosis in chronic granulomatous disease (CGD). J Leukoc Biol 73:591–599, Medline DOI  10.1189/jlb.1202599 PubMedGoogle Scholar
  22. 22.
    Brown SJ, Mayer L (2007) The immune response in inflammatory bowel disease. Am J Gastroenterol 102:2058–2069, Medline DOI  10.1111/j.1572-0241.2007.01343.x PubMedGoogle Scholar
  23. 23.
    Bryk R, Griffin P, Nathan C (2000) Peroxynitrite reductase activity of bacterial peroxiredoxins. Nature 407:211–215, Medline DOI  10.1038/35025109 PubMedGoogle Scholar
  24. 24.
    Cheng G, Cao Z, Xu X, Meir EGV, Lambeth JD (2001) Homologs of gp91phox: cloning and tissue expression of Nox3, Nox4, and Nox5. Gene 269:131–140, Medline DOI  10.1016/S0378-1119(01)00449-8 PubMedGoogle Scholar
  25. 25.
    Cheng G, Diebold BA, Hughes Y, Lambeth JD (2006) Nox1-dependent reactive oxygen generation is regulated by Rac1. J Biol Chem 281:17718–17726, Medline DOI  10.1074/jbc.M512751200 PubMedGoogle Scholar
  26. 26.
    Cheng G, Lambeth JD (2004) NOXO1, Regulation of lipid binding, localization, and activation of Nox1 by the phox homology (PX) domain. J Biol Chem 279:4737–4742, Medline DOI  10.1074/jbc.M305968200 PubMedGoogle Scholar
  27. 27.
    Correa P (1992) Human gastric carcinogenesis: a multistep and multifactorial process—First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 52:6735–6740, MedlinePubMedGoogle Scholar
  28. 28.
    Correa P, Houghton J (2007) Carcinogenesis of Helicobacter pylori. Gastroenterology 133:659–672, Medline DOI  10.1053/j.gastro.2007.06.026 PubMedGoogle Scholar
  29. 29.
    Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867, Medline DOI  10.1038/nature01322 PubMedGoogle Scholar
  30. 30.
    Covacci A, Telford JL, Giudice GD, Parsonnet J, Rappuoli R (1999) Helicobacter pylori virulence and genetic geography. Science 284:1328–1333, Medline DOI  10.1126/science.284.35418.1328 PubMedGoogle Scholar
  31. 31.
    de Carvalho DD, Sadok A, Bourgarel-Rey V, Gattacceca F, Penel C, Lehmann M, Kovacic H. (2008) Nox1 downstream of 12-lipoxygenase controls cell proliferation but not cell spreading of colon cancer cells. Int J Cancer 122:1757–1764PubMedGoogle Scholar
  32. 32.
    Davies GR, Simmonds NJ, Stevens TR, Sheaff MT, Banatvala N, Laurenson IF, Blake DR, Rampton DS (1994) Helicobacter pylori stimulates antral mucosal reactive oxygen metabolite production in vivo. Gut 35:179–185, Medline DOI  10.1136/gut.35.2.179 PubMedGoogle Scholar
  33. 33.
    De Deken X, Wang D, Many M-C, Costagliola S, Libert F, Vassart G, Dumont JE, Miot F (2000) Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family. J Biol Chem 275:23227–23233, Medline DOI  10.1074/jbc.M000916200 PubMedGoogle Scholar
  34. 34.
    Dröge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95, MedlinePubMedGoogle Scholar
  35. 35.
    Dupuy C, Pomerance M, Ohayon R, Noel-Hudson M-S, Deme D, Chaaraoui M, Francon J, Virion A (2000) Thyroid oxidase (THOX2) gene expression in the rat thyroid cell Line FRTL-5. Biochem Biophys Res Commun 277:287–292, Medline DOI  10.1006/bbrc.2000.3671 PubMedGoogle Scholar
  36. 36.
    El-Omar EM, Rabkin CS, Gammon MD, Vaughan TL, Risch HA, Schoenberg JB, Stanford JL, Mayne ST, Goedert J, Blot WJ, Fraumeni JF Jr, Chow WH (2003) Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 124:1193–1201, Medline DOI  10.1016/S0016-5085(03)00157-4 PubMedGoogle Scholar
  37. 37.
    El Hassani RA, Benfares N, Caillou B, Talbot M, Sabourin J-C, Belotte V, Morand S, Gnidehou S, Agnandji D, Ohayon R, Kaniewski J, Noel-Hudson M-S, Bidart J-M, Schlumberger M, Virion A, Dupuy C (2005) Dual oxidase2 is expressed all along the digestive tract. Am J Physiol Gastrointest Liver Physiol 288:G933–G942, Medline DOI  10.1152/ajpgi.00198.2004 PubMedGoogle Scholar
  38. 38.
    Evans DJ Jr, Evans DG, Takemura T, Nakano H, Lampert HC, Graham DY, Granger DN, Kvietys PR (1995) Characterization of a Helicobacter pylori neutrophil-activating protein. Infect Immun 63:2213–2220, MedlinePubMedGoogle Scholar
  39. 39.
    Farinati F, Cardin R, Degan P, Rugge M, Di Mario F, Bonvicini P, Naccarato R (1998) Oxidative DNA damage accumulation in gastric carcinogenesis. Gut 42:351–356, MedlinePubMedCrossRefGoogle Scholar
  40. 40.
    Figueiredo C, Machado JC, Pharoah P, Seruca R, Sousa S, Carvalho R, Capelinha AF, Quint W, Caldas C, van Doorn L-J, Carneiro F, Sobrinho-Simoes M (2002) Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst 94:1680–1687, MedlinePubMedGoogle Scholar
  41. 41.
    Fox JG, Wang TC (2001) Helicobacter pylori-not a good bug after all!. N Engl J Med 345:829–832, Medline DOI  10.1056/NEJM200109133451111 PubMedGoogle Scholar
  42. 42.
    Fukata M, Abreu MT (2008) Role of Toll-like receptors in gastrointestinal malignancies. Oncogene 27:234–243, Medline DOI  10.1038/sj.onc.1210908 PubMedGoogle Scholar
  43. 43.
    Fukuyama M, Rokutan K, Sano T, Miyake H, Shimada M, Tashiro S (2005) Overexpression of a novel superoxide-producing enzyme, NADPH oxidase 1, in adenoma and well differentiated adenocarcinoma of the human colon. Cancer Lett 221:97–104, Medline DOI  10.1016/j.canlet.2004.08.031 PubMedGoogle Scholar
  44. 44.
    Gallin JI, Buescher ES (1983) Abnormal regulation of inflammatory skin responses in male patients with chronic granulomatous disease. Inflammation 7:227–232, Medline DOI  10.1007/BF00917259 PubMedGoogle Scholar
  45. 45.
    Geiszt M, Lekstrom K, Brenner S, Hewitt SM, Dana R, Malech HL, Leto TL (2003) NAD(P)H oxidase 1, a product of differentiated colon epithelial cells, can partially replace glycoprotein 91phox in the regulated production of superoxide by phagocytes. J Immunol 171:299–306, MedlinePubMedGoogle Scholar
  46. 46.
    Geiszt M, Lekstrom K, Witta J, Leto TL (2003) Proteins homologous to p47phox and p67phox support superoxide production by NAD(P)H oxidase 1 in colon epithelial cells. J Biol Chem 278:20006–20012, Medline DOI  10.1074/jbc.M301289200 PubMedGoogle Scholar
  47. 47.
    Geiszt M, Leto TL (2004) The Nox family of NAD(P)H oxidases: host defense and beyond. J Biol Chem 279:51715–51718, Medline DOI  10.1074/jbc.R400024200 PubMedGoogle Scholar
  48. 48.
    Geiszt M, Witta J, Baffi J, Lekstrom K, Leto TL (2003) Dual oxidases represent novel hydrogen peroxide sources supporting mucosal surface host defense. FASEB J 17:1502–1504, MedlinePubMedGoogle Scholar
  49. 49.
    Gewirtz AT, Navas TA, Lyons S, Godowski PJ, Madara JL (2001) Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J Immunol 167:1882–1885, MedlinePubMedGoogle Scholar
  50. 50.
    Goodwin CS, Armstrong JA, Marshall BJ (1986) Campylobacter pyloridis, gastritis, and peptic ulceration. J Clin Pathol 39:353–365, Medline DOI  10.1136/jcp.39.4.353 PubMedGoogle Scholar
  51. 51.
    Grandvaux N, Soucy-Faulkner A, Fink K (2007) Innate host defense: Nox and Duox on phox's tail. Biochimie 89:1113–1122, Medline DOI  10.1016/j.biochi.2007.04.008 PubMedGoogle Scholar
  52. 52.
    Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, Kagnoff MF, Karin M (2004) IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118:285–296, Medline DOI  10.1016/j.cell.2004.07.013 PubMedGoogle Scholar
  53. 53.
    Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, Taite H, Scoular R, Miller A, Reeve AE (1998) E-cadherin germline mutations in familial gastric cancer. Nature 392:402–405, Medline DOI  10.1038/32918 PubMedGoogle Scholar
  54. 54.
    Hampton MB, Vissers MCM, Keenan JI, Winterbourn CC (2002) Oxidant-mediated phosphatidylserine exposure and macrophage uptake of activated neutrophils: possible impairment in chronic granulomatous disease. J Leukoc Biol 71:775–781, MedlinePubMedGoogle Scholar
  55. 55.
    Hanna IR, Hilenski LL, Dikalova A, Taniyama Y, Dikalov S, Lyle A, Quinn MT, Lassegue B, Griendling KK (2004) Functional association of nox1 with p22phox in vascular smooth muscle cells. Free Radic Biol Med 37:1542–1549, Medline DOI  10.1016/j.freeradbiomed.2004.08.011 PubMedGoogle Scholar
  56. 56.
    Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A (2001) The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410:1099–1103, Medline DOI  10.1038/35074106 PubMedGoogle Scholar
  57. 57.
    Hershberg RM (2002) The epithelial cell cytoskeleton and intracellular trafficking: V. Polarized compartmentalization of antigen processing and Toll-like receptor signaling in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 283:G833–G839, MedlinePubMedGoogle Scholar
  58. 58.
    Houghton J, Wang TC (2005) Helicobacter pylori and gastric cancer: a new paradigm for inflammation-associated epithelial cancers. Gastroenterology 128:1567–1578, Medline DOI  10.1053/j.gastro.2005.03.037 PubMedGoogle Scholar
  59. 59.
    Huang JS, Noack D, Rae J, Ellis BA, Newbury R, Pong AL, Lavine JE, Curnutte JT, Bastian J (2004) Chronic granulomatous disease caused by a deficiency in p47(phox) mimicking Crohn's disease. Clin Gastroenterol Hepatol 2:690–695, Medline DOI  10.1016/S1542-3565(04)00292-7 PubMedGoogle Scholar
  60. 60.
    Huber MA, Azoitei N, Baumann B, Grunert S, Sommer A, Pehamberger H, Kraut N, Beug H, Wirth T (2004) NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 114:569–581, MedlinePubMedGoogle Scholar
  61. 61.
    Itzkowitz SH, Yio X (2004) Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol 287:G7–G17, Medline DOI  10.1152/ajpgi.00079.2004 PubMedGoogle Scholar
  62. 62.
    Jackson SH, Devadas S, Kwon J, Pinto LA, Williams MS (2004) T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation. Nat Immunol 5:818–827, Medline DOI  10.1038/ni1096 PubMedGoogle Scholar
  63. 63.
    Karin M, Lawrence T, Nizet V (2006) Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 124:823–835, Medline DOI  10.1016/j.cell.2006.02.016 PubMedGoogle Scholar
  64. 64.
    Kawahara T, Kohjima M, Kuwano Y, Mino H, Teshima-Kondo S, Takeya R, Tsunawaki S, Wada A, Sumimoto H, Rokutan K (2005) Helicobacter pylori lipopolysaccharide activates Rac1 and transcription of NADPH oxidase Nox1 and its organizer NOXO1 in guinea pig gastric mucosal cells. Am J Physiol Cell Physiol 288:C450–C457, Medline DOI  10.1152/ajpcell.00319.2004 PubMedGoogle Scholar
  65. 65.
    Kawahara T, Kuwano Y, Teshima-Kondo S, Takeya R, Sumimoto H, Kishi K, Tsunawaki S, Hirayama T, Rokutan K (2004) Role of nicotinamide adenine dinucleotide phosphate oxidase 1 in oxidative burst response to Toll-like receptor 5 signaling in large intestinal epithelial cells. J Immunol 172:3051–3058, MedlinePubMedGoogle Scholar
  66. 66.
    Kawahara T, Ritsick D, Cheng G, Lambeth JD (2005) Point mutations in the proline-rich region of p22phox are dominant inhibitors of Nox1- and Nox2-dependent reactive oxygen generation. J Biol Chem 280:31859–31869, Medline DOI  10.1074/jbc.M501882200 PubMedGoogle Scholar
  67. 67.
    Kawahara T, Teshima S, Oka A, Sugiyama T, Kishi K, Rokutan K (2001) Type I Helicobacter pylori lipopolysaccharide stimulates Toll-like receptor 4 and activates mitogen oxidase 1 in gastric pit cells. Infect Immun 69:4382–4389, Medline DOI  10.1128/IAI.69.7.4382-4389.2001 PubMedGoogle Scholar
  68. 68.
    Keenan JI, Peterson Ii RA, Hampton MB (2005) NADPH oxidase involvement i n the pathology of Helicobacter pylori infection. Free Radic Biol Med 38:1188–1196, Medline DOI  10.1016/j.freeradbiomed.2004.12.025 PubMedGoogle Scholar
  69. 69.
    Kikuchi H, Hikage M, Miyashita H, Fukumoto M (2000) NADPH oxidase subunit, gp91phox homologue, preferentially expressed in human colon epithelial cells. Gene 254:237–243, Medline DOI  10.1016/S0378-1119(00)00258-4 PubMedGoogle Scholar
  70. 70.
    Kruidenier L, Verspaget HW (2002) Oxidative stress as a pathogenic factor in inflammatory bowel disease - radicals or ridiculous? Aliment Pharmacol Ther 16:1997–2015, Medline DOI  10.1046/j.1365-2036.2002.01378.x PubMedGoogle Scholar
  71. 71.
    Kuwano Y, Kawahara T, Yamamoto H, Teshima-Kondo S, Tominaga K, Masuda K, Kishi K, Morita K, Rokutan K (2006) Interferon-γ activates transcription of NADPH oxidase 1 gene and upregulates production of superoxide anion by human large intestinal epithelial cells. Am J Physiol Cell Physiol 290:C433–C443, Medline DOI  10.1152/ajpcell.00135.2005 PubMedGoogle Scholar
  72. 72.
    Lambeth JD (2004) NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4:181–189, Medline DOI  10.1038/nri1312 PubMedGoogle Scholar
  73. 73.
    Lambeth JD (2007) Nox enzymes, ROS, and chronic disease: an example of antagonistic pleiotropy. Free Radic Biol Med 43:332–347, Medline DOI  10.1016/j.freeradbiomed.2007.03.027 PubMedGoogle Scholar
  74. 74.
    Marciano BE, Rosenzweig SD, Kleiner DE, Anderson VL, Darnell DN, Anaya-O'Brien S, Hilligoss DM, Malech HL, Gallin JI, Holland SM (2004) Gastrointestinal involvement in chronic granulomatous disease. Pediatrics 114:462–468, Medline DOI  10.1542/peds.114.2.462 PubMedGoogle Scholar
  75. 75.
    Marshall B, Warren JR (1984) Undefined curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 323:1311–1315, DOI  10.1016/S0140-6736(84)91816-6 Google Scholar
  76. 76.
    Matsukura N, Suzuki K, Kawachi T, Aoyagi M, Sugimura T, Kitaoka H, Numajiri H, Shirota A, Itabashi M, Hirota T (1980) Distribution of marker enzymes and mucin in intestinal metaplasia in human stomach and relation to complete and incomplete types of intestinal metaplasia to minute gastric carcinomas. J Natl Cancer Inst 65:231–240, MedlinePubMedGoogle Scholar
  77. 77.
    Menon SG, Goswami PC (2006) A redox cycle within the cell cycle: ring in the old with the new. Oncogene 26:1101–1109, Medline DOI  10.1038/sj.onc.1209895 PubMedGoogle Scholar
  78. 78.
    Miyano K, Ueno N, Takeya R, Sumimoto H (2006) Direct involvement of the small GTPase Rac in activation of the superoxide-producing NADPH oxidase Nox1. J Biol Chem 281:21857–21868, Medline DOI  10.1074/jbc.M513665200 PubMedGoogle Scholar
  79. 79.
    Moreno JC, Visser TJ (2007) New phenotypes in thyroid dyshormonogenesis: hypothyroidism due to DUOX2 mutations. Endocr Dev 10:99–117, MedlinePubMedCrossRefGoogle Scholar
  80. 80.
    Morgenstern DE, Gifford MAC, Li LL, Doerschuk CM, Dinauer MC (1997) Absence of respiratory burst in X-linked chronic granulomatous disease mice leads to abnormalities in both host defense and inflammatory response to Aspergillus fumigatus. J Exp Med 185:207–218, Medline DOI  10.1084/jem.185.2.207 PubMedGoogle Scholar
  81. 81.
    Moss SF, Blaser, Martin J (2005) Mechanisms of disease: inflammation and the origins of cancer. Nat Clin Pract Oncol 2:90–97, Medline DOI  10.1038/ncponc0081 PubMedGoogle Scholar
  82. 82.
    Mutoh H, Sakurai S, Satoh K, Tamada K, Kita H, Osawa H, Tomiyama T, Sato Y, Yamamoto H, Isoda N, Yoshida T, Ido K, Sugano K (2004) Development of gastric carcinoma from intestinal metaplasia in Cdx2-transgenic mice. Cancer Res 64:7740–7747, Medline DOI  10.1158/0008-5472.CAN-04-1617 PubMedGoogle Scholar
  83. 83.
    Naumann M, Crabtree JE (2004) Helicobacter pylori-induced epithelial cell signalling in gastric carcinogenesis. Trends in Microbiology 12:29–36, Medline DOI  10.1016/j.tim.2003.11.005 PubMedGoogle Scholar
  84. 84.
    Nomura A, Stemmermann GN, Chyou PH, Kato I, Perez-Perez GI, Blaser MJ (1991) Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med 325:1132–1136, MedlinePubMedGoogle Scholar
  85. 85.
    Obst B, Wagner S, Sewing KF, Beil W (2000) Helicobacter pylori causes DNA damage in gastric epithelial cells. Carcinogenesis 21:1111–1115, Medline DOI  10.1093/carcin/21.6.1111 PubMedGoogle Scholar
  86. 86.
    Panchal PC, Forman J, Blumberg DR, Wilson KT (2003) Helicobacter pylori infection: pathogenesis. Curr Opin Gastroenterol 19:1–3, Medline DOI  10.1097/00001574-200301000-00002 Google Scholar
  87. 87.
    Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N, Sibley RK (1991) Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 325:1127–1131, MedlinePubMedGoogle Scholar
  88. 88.
    Perner A, Andresen L, Pedersen G, Rask-Madsen J (2003) Superoxide production and expression of NAD(P)H oxidases by transformed and primary human colonic epithelial cells. Gut 52:231–236, Medline DOI  10.1136/gut.52.2.231 PubMedGoogle Scholar
  89. 89.
    Jenks PJ, Jeremy AHT, Robinson PA, Walker MM, Crabtree JE (2003) Long-term infection with Helicobacter felis and inactivation of the tumour suppressor gene p53 cumulatively enhance the gastric mutation frequency in Big BlueÒ transgenic mice. The Journal of Pathology 201:596–602, Medline DOI  10.1002/path.1488 PubMedGoogle Scholar
  90. 90.
    Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y (2004) NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 431:461–466, Medline DOI  10.1038/nature02924 PubMedGoogle Scholar
  91. 91.
    Ramarao N, Gray-Owen SD, Meyer TF (2000) Helicobacter pylori induces but survives the extracellular release of oxygen radicals from professional phagocytes using its catalase activity. Mol Microbiol 38:103–113, Medline DOI  10.1046/j.1365-2958.2000.02114.x PubMedGoogle Scholar
  92. 92.
    Rezaie A, Parker R, Abdollahi M (2007) Oxidative stress and pathogenesis of inflammatory bowel disease: an epiphenomenon or the cause? Dig Dis Sci 52:2015–2021, Medline DOI  10.1007/s10620-006-9622-2 PubMedGoogle Scholar
  93. 93.
    Peek RMJEC Jr (2006) Helicobacter infection and gastric neoplasia. The J Pathol 208:233–248, Medline DOI  10.1002/path.1868 Google Scholar
  94. 94.
    Rokutan K, Kawahara T, Kuwano Y, Tominaga K, Sekiyama A, Teshima-Kondo S (2006) NADPH oxidases in the gastrointestinal tract: a potential role of Nox1 in innate immune response and carcinogenesis. Antioxid Redox Signal 8:1573–1582, Medline DOI  10.1089/ars.2006.8.1573 PubMedGoogle Scholar
  95. 95.
    Salles N, Szanto I, Herrmann F, Armenian B, Stumm M, Stauffer E, Michel JP, Krause KH (2005) Expression of mRNA for ROS-generating NADPH oxidases in the aging stomach. Exp Gerontol 40:353–357, Medline DOI  10.1016/j.exger.2005.01.007 PubMedGoogle Scholar
  96. 96.
    Sansonetti PJ (2006) The innate signaling of dangers and the dangers of innate signaling. Nat Immunol 7:1237–1242, Medline DOI  10.1038/ni1420 PubMedGoogle Scholar
  97. 97.
    Sansonetti PJ (2004) War and peace at mucosal surfaces. Nat Rev Immunol 4:953–964, Medline DOI  10.1038/nri1499 PubMedGoogle Scholar
  98. 98.
    Satin B, Del Giudice G, Della Bianca V, Dusi S, Laudanna C, Tonello F, Kelleher D, Rappuoli R, Montecucco C, Rossi F (2000) The neutrophil-activating protein (HP-NAP) of Helicobacter pylori is a protective antigen and a major virulence factor. J Exp Med 191:1467–1476, Medline DOI  10.1084/jem.191.9.1467 PubMedGoogle Scholar
  99. 99.
    SchmaussEr B, Andrulis M, Endrich S, Lee SK, Josenhans C, Muller-Hermelink HK, Eck M (2004) Expression and subcellular distribution of toll-like receptors TLR4, TLR5 and TLR9 on the gastric epithelium in Helicobacter pylori infection. Clin Exp Immunol 136:521–526, Medline DOI  10.1111/j.1365-2249.2004.02464.x PubMedGoogle Scholar
  100. 100.
    Silberg DG, Sullivan J, Kang E, Swain GP, Moffett J, Sund NJ, Sackett SD, Kaestner KH (2002) Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice. Gastroenterology 122:689–696, Medline DOI  10.1053/gast.2002.31902 PubMedGoogle Scholar
  101. 101.
    Suh YA, Arnold RS, Lassegue B, Shi J, Xu X, Sorescu D, Chung AB, Griendling KK, Lambeth JD (1999) Cell transformation by the superoxide-generating oxidase Mox1. Nature 401:79–82, Medline DOI  10.1038/43459 PubMedGoogle Scholar
  102. 102.
    Suzuki H, Miura S, Imaeda H, Suzuki M, Han JY, Mori M, Fukumura D, Tsuchiya M, Ishii H (1996) Enhanced levels of chemiluminescence and platelet activating factor in urease-positive gastric ulcers. Free Radic Biol Med 20:449–454, Medline DOI  10.1016/0891-5849(96)02048-5 PubMedGoogle Scholar
  103. 103.
    Szanto I, Rubbia-Brandt L, Kiss P, Steger K, Banfi B, Kovari E, Herrmann F, Hadengue A, Krause KH (2005) Expression of NOX1, a superoxide-generating NADPH oxidase, in colon cancer and inflammatory bowel disease. J Pathol 207:164–176, Medline DOI  10.1002/path.1824 PubMedGoogle Scholar
  104. 104.
    Takeya R, Ueno N, Kami K, Taura M, Kohjima M, Izaki T, Nunoi H, Sumimoto H (2003) Novel human homologues of p47phox and p67phox participate in activation of superoxide-producing NADPH oxidases. J Biol Chem 278:25234–25246, Medline DOI  10.1074/jbc.M212856200 PubMedGoogle Scholar
  105. 105.
    Teshima S, Kutsumi H, Kawahara T, Kishi K, Rokutan K (2000) Regulation of growth and apoptosis of cultured guinea pig gastric mucosal cells by mitogenic oxidase 1. Am J Physiol Gastrointest Liver Physiol 279:G1169–G1176, MedlinePubMedGoogle Scholar
  106. 106.
    Teshima S, Rokutan K, Nikawa T, Kishi K (1998) Guinea pig gastric mucosal cells produce abundant superoxide anion through an NADPH oxidase-like system. Gastroenterology 115:1186–1196, Medline DOI  10.1016/S0016-5085(98)70090-3 PubMedGoogle Scholar
  107. 107.
    Tominaga K, Kawahara T, Sano T, Toida K, Kuwano Y, Sasaki H, Kawai T, T eshima-Kondo S, Rokutan K (2007) Evidence for cancer-associated expression of NADPH oxidase 1 (Nox1)-based oxidase system in the human stomach. Free Radic Biol Med 43:1627–1638, Medline DOI  10.1016/j.freeradbiomed.2007.08.029 PubMedGoogle Scholar
  108. 108.
    Tonello F, Dundon WG, Satin B, Molinari M, Tognon G, Grandi G, Del Giudice G, Rappuoli R, Montecucco C (1999) The Helicobacter pylori neutrophil-activating protein is an iron-binding protein with dodecameric structure. Mol Microbiol 34:238–246, Medline DOI  10.1046/j.1365-2958.1999.01584.x PubMedGoogle Scholar
  109. 109.
    Touati E, Michel V, Thiberge J-M, Wuscher N, Huerre M, Labigne A (2003) Chronic Helicobacter pylori infections induce gastric mutations in mice. Gastroenterology 124:1408–1419, Medline DOI  10.1016/S0016-5085(03)00266-X PubMedGoogle Scholar
  110. 110.
    Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, Taniyama K, Sasaki N, Schlemper RJ (2001) Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 345:784–789, Medline DOI  10.1056/NEJMoa001999 PubMedGoogle Scholar
  111. 111.
    Ueyama T, Geiszt M, Leto TL (2006) Involvement of Rac1 in activation of multicomponent Nox1- and Nox3-based NADPH oxidases. Mol Cell Biol 26:2160–2174, Medline DOI  10.1128/MCB.26.6.2160-2174.2006 PubMedGoogle Scholar
  112. 112.
    Ushio-Fukai M (2006) Redox signaling in angiogenesis: role of NADPH oxidase. Cardiovascular Res 71:226–235, Medline DOI  10.1016/j.cardiores.2006.04.015 Google Scholar
  113. 113.
    Valente AJ, Zhou Q, Lu Z, He W, Qiang M, Ma W, Li G, Wang L, Banfi B, Steger K, Krause KH, Clark RA, Li S (2007) Regulation of NOX1 expression by GATA, HNF-1α, and Cdx transcription factors. Free Radic Biol Med 22:22Google Scholar
  114. 114.
    Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, Athman R, Memet S, Huerre MR, Coyle AJ, DiStefano PS, Sansonetti PJ, Labigne A, Bertin J, Philpott DJ, Ferrero RL (2004) Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol 5:1166–1174, Medline DOI  10.1038/ni1131 PubMedGoogle Scholar
  115. 115.
    Wilson KT, Crabtree JE (2007) Immunology of Helicobacter pylori: insights into the failure of the immune response and perspectives on vaccine studies. Gastroenterology 133:288–308, Medline DOI  10.1053/j.gastro.2007.05.008 PubMedGoogle Scholar
  116. 116.
    Xia C, Meng Q, Liu L-Z, Rojanasakul Y, Wang X-R, Jiang B-H (2007) Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Res 67:10823–10830, Medline DOI  10.1158/0008-5472.CAN-07-0783 PubMedGoogle Scholar
  117. 117.
    Xu H, Chaturvedi R, Cheng Y, Bussiere FI, Asim M, Yao MD, Potosky D, Meltzer SJ, Rhee JG, Kim SS, Moss SF, Hacker A, Wang Y, Casero RA Jr, Wilson KT (2004) Spermine oxidation induced by Helicobacter pylori results in apoptosis and DNA damage: implications for gastric carcinogenesis. Cancer Res 64:8521–8525, Medline DOI  10.1158/0008-5472.CAN-04-3511 PubMedGoogle Scholar
  118. 118.
    Yang S, Panoskaltsis-Mortari A, Shukla M, Blazar BR, Haddad IY (2002) Exuberant inflammation in nicotinamide adenine dinucleotide phosphate-oxidase-deficient mice after allogeneic marrow transplantation. J Immunol 168:5840–5847, MedlinePubMedGoogle Scholar
  119. 119.
    Yuasa Y (2003) Control of gut differentiation and intestinal-type gastric carcinogenesis. Nat Rev Cancer 3:592–600, Medline DOI  10.1038/nrc1141 PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Kazuhito Rokutan
    • 1
    Email author
  • Tsukasa Kawahara
    • 1
  • Yuki Kuwano
    • 1
  • Kumiko Tominaga
    • 1
  • Keisei Nishida
    • 1
  • Shigetada Teshima-Kondo
    • 1
  1. 1.Department of Stress Science, Institute of Health BiosciencesUniversity of Tokushima Graduate SchoolTokushimaJapan

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