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Coexpression of Interleukin-8 and Inducible Nitric Oxide Synthase in Gastric Mucosa Infected with cagA+ Helicobacter pylori

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Abstract

The cagA-positive Helicobacter pylori strains are thought to be able to induce interleukin-8 expression and to be associated with gastroduodenal diseases. Inducible nitric oxide synthase (iNOS) may be involved in inflammatory pathogenesis. Our aim was to investigate the interrelationships between cagA and the expression of interleukin-8 and iNOS messenger RNAs, and with the type and degree of inflammation in gastric mucosa. In biopsies from 108 Chinese patients, the cagA, 16S rRNA, interleukin-8, and iNOS mRNAs were analyzed using reverse-transcription polymerase chain reaction. Specimens infected with cagA-positive strains had significantly more severe infiltration by mononuclear and polymorphonuclear leukocytes and more frequently expressed interleukin-8 and iNOS mRNAs than those infected with cagA-negative strains. iNOS and interleukin-8 mRNAs were significantly more frequently expressed together in the specimens with moderate or severe inflammation than in those with normal mucosa or mild inflammation. Our data suggest that interleukin-8 and excess nitric oxide play important roles in the pathogenesis of H. pylori-associated gastroduodenal diseases.

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REFERENCES

  1. Mobley HL: Helicobacter pylori factors associated with disease development. Gastroenterology 113:S21-S28, 1997

    PubMed  Google Scholar 

  2. Nomura A, Stemmermann GN, Chyou PH, Kato I, Perez Perez GI, Blaser MJ: Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med 325:1132-1136, 1991

    PubMed  Google Scholar 

  3. Parsonnet J, Harris RA, Hack HM, Owens DK: Modelling cost-effectiveness of Helicobacter pylori screening to prevent gastric cancer: A mandate for clinical trials. Lancet 348:150-154, 1996

    PubMed  Google Scholar 

  4. Tummuru MK, Cover TL, Blaser MJ: Cloning and expression of a high-molecular-mass major antigen of Helicobacter pylori: Evidence of linkage to cytotoxin production. Infect Immun 61:1799-1809, 1993

    PubMed  Google Scholar 

  5. Crabtree JE, Taylor JD, Wyatt JI, Heatley RV, Shallcross TM, Tompkins DS, Rathbone BJ: Mucosal IgA recognition of Helicobacter pylori 120 kDa protein, peptic ulceration, and gastric pathology. Lancet 338:332-335, 1991

    PubMed  Google Scholar 

  6. Blaser MJ, Perez PG, Kleanthous H, Cover TL, Peek RM, Chyou PH, Stemmermann GN, Nomura A: Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res 55:2111-2115, 1995

    PubMed  Google Scholar 

  7. Maeda S, Ogura K, Yoshida H, Kanai F, Ikenoue T, Kato N, Shiratori Y, Omata M: Major virulence factors, VacA and CagA, are commonly positive in Helicobacter pylori isolates in Japan. Gut 42:338-343, 1998

    PubMed  Google Scholar 

  8. Larsen CG, Anderson AO, Appella E, Oppenheim JJ, Matsushima K: The neutrophil-activating protein (NAP-1) is also chemotactic for T lymphocytes. Science 243:1464-1466, 1989

    PubMed  Google Scholar 

  9. Kitadai Y, Haruma K, Sumii K, Yamamoto S, Ue T, Yokozaki H, Yasui W, Ohmoto Y, Kajiyama G, Fidler IJ, Tahara E: Expression of interleukin-8 correlates with vascularity in human gastric carcinomas. Am J Pathol 152:93-100, 1998

    PubMed  Google Scholar 

  10. Yamaoka Y, Kita M, Kodama T, Sawai N, Tanahashi T, Kashima K, Imanishi J: Chemokines in the gastric mucosa in Helicobacter pylori infection. Gut 42:609-617, 1998

    PubMed  Google Scholar 

  11. Ando T, Kusugami K, Ohsuga M, Shinoda M, Sakakibara M, Saito H, Fukatsu A, Ichiyama S, Ohta M: Interleukin-8 activity correlates with histological severity in Helicobacter pyloriassociated antral gastritis. Am J Gastroenterol 91:1150-1156, 1996

    PubMed  Google Scholar 

  12. Crabtree JE, Farmery SM, Lindley IJ, Figura N, Peichl P, Tompkins DS: CagA/cytotoxic strains of Helicobacter pylori and interleukin-8 in gastric epithelial cell lines. J Clin Pathol 47:945-950, 1994

    PubMed  Google Scholar 

  13. Crabtree JE, Covacci A, Farmery SM, Xiang Z, Tompkins DS, Perry S, Lindley IJ, Rappuoli R: Helicobacter pylori induced interleukin-8 expression in gastric epithelial cells is associated with CagA positive phenotype. J Clin Pathol 48:41-45, 1995

    PubMed  Google Scholar 

  14. Yamaoka Y, Kita M, Kodama T, Sawai N, Kashima K, Imanishi J: Induction of various cytokines and development of severe mucosal inflammation by cagA gene positive Helicobacter pylori strains. Gut 41:442-451, 1997

    PubMed  Google Scholar 

  15. Sharma SA, Tummuru MK, Miller GG, Blaser MJ: Interleukin-8 response of gastric epithelial cell lines to Helicobacter pylori stimulation in vitro. Infect Immun 63:1681-1687, 1995

    PubMed  Google Scholar 

  16. Tummuru MK, Sharma SA, Blaser MJ: Helicobacter pylori picB, a homologue of the Bordetella pertussis toxin secretion protein, is required for induction of IL-8 in gastric epithelial cells. Mol Microbiol 18:867-876, 1995

    PubMed  Google Scholar 

  17. Ohshima H, Bartsch H: Chronic infections and inflammatory processes as cancer risk factors: Possible role of nitric oxide in carcinogenesis. Mutat Res 305:253-264, 1994

    PubMed  Google Scholar 

  18. Pignatelli B, Bancel B, Estève J, Malaveille C, Calmels S, Correa P, Patricot LM, Laval M, Lyandrat N, Ohshima H: Inducible nitric oxide synthase, anti-oxidant enzymes and Helicobacter pylori infection in gastritis and gastric precancerous lesions in humans. Eur J Cancer Prev 7:439-447, 1998

    PubMed  Google Scholar 

  19. Pignatelli B, Bancel B, Malaveille C, Calmels S, Correa PM, Patricot LM, Laval M, Lyandrat N, Ohshima H: Helicobacter pylori infection oxidative stress and stomach cancer. In International Agency for Research on Cancer Biennial Report 1994/1995, Lyon, IARC, 1995, pp 101-102

    Google Scholar 

  20. Mannick EE, Bravo LE, Zarama G, Realpe JL, Zhang XJ, Ruiz B, Fontham ET, Mera R, Miller MJ, Correa P: Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: Effect of antibiotics and antioxidants. Cancer Res 56:3238-3243, 1996

    PubMed  Google Scholar 

  21. Bruch Gerharz D, Fehsel K, Suschek C, Michel G, Ruzicka T, Kolb Bachofen V: A proinflammatory activity of interleukin 8 in human skin: Expression of the inducible nitric oxide synthase in psoriatic lesions and cultured keratinocytes. J Exp Med 184:2007-2012, 1996

    PubMed  Google Scholar 

  22. Villarete LH, Remick DG: Nitric oxide regulation of interleukin-8 gene expression. Shock 7:29-35, 1997

    PubMed  Google Scholar 

  23. Andrew PJ, Harant H, Lindley IJ: Nitric oxide regulates IL-8 expression in melanoma cells at the transcriptional level. Biochem Biophys Res Commun 214:949-956, 1995

    Article  PubMed  Google Scholar 

  24. McCall TB, Palmer RM, Moncada S: Interleukin-8 inhibits the induction of nitric oxide synthase in rat peritoneal neutrophils. Biochem Biophys Res Commun 186:680-685, 1992

    PubMed  Google Scholar 

  25. Peek RM Jr, Miller GG, Tham KT, Perez Perez GI, Cover TL, Atherton JC, Dunn GD, Blaser MJ: Detection of Helicobacter pylori gene expression in human gastric mucosa. J Clin Microbiol 33:28-32, 1995

    PubMed  Google Scholar 

  26. Gray SF, Wyatt JI, Rathbone BJ: Simplified techniques for identifying Campylobacter pyloridis. J Clin Pathol 39:1279, 1986

    PubMed  Google Scholar 

  27. Price AB: The Sydney System: Histological division. J Gastroenterol Hepatol 6:209-222, 1991

    PubMed  Google Scholar 

  28. Peek-RM J, Moss SF, Tham KT, Perez PG, Wang S, Miller GG, Atherton JC, Holt PR, Blaser MJ: Helicobacter pylori cagA1 strains and dissociation of gastric epithelial cell proliferation from apoptosis. J Natl Cancer Inst 89:863-868, 1997

    PubMed  Google Scholar 

  29. Peek-RM J, Miller GG, Tham KT, Perez PG, Zhao X, Atherton JC, Blaser MJ: Heightened inflammatory response and cytokine expression in vivo to cagA1 Helicobacter pylori strains. Lab Invest 73:760-770, 1995

    PubMed  Google Scholar 

  30. Ambs S, Merriam WG, Bennett WP, Felley BE, Ogunfusika MO, Oser SM, Klein S, Shields PG, Billiar TR, Harris CC: Frequent nitric oxide synthase-2 expression in human colon adenomas: Implication for tumor angiogenesis and colon cancer progression. Cancer Res 58:334-341, 1998

    PubMed  Google Scholar 

  31. Weel JF, van der Hulst RW, Gerrits Y, Roorda P, Feller M, Dankert J, Tytgat GN, van der Ende A: The interrelationship between cytotoxin-associated gene A, vacuolating cytotoxin, and Helicobacter pylori-related diseases. J Infect Dis 173:1171-1175, 1996

    PubMed  Google Scholar 

  32. Pan ZJ, van der Hulst RW, Feller M, Xiao SD, Tytgat GN, Dankert J, van der Ende A: Equally high prevalences of infection with cagA-positive Helicobacter pylori in Chinese patients with peptic ulcer disease and those with chronic gastritis-associated dyspepsia. J Clin Microbiol 35:1344-1347, 1997

    PubMed  Google Scholar 

  33. Miehlke S, Kibler K, Kim JG, Figura N, Small SM, Graham DY, Go MF: Allelic variation in the cagA gene of Helicobacter pylori obtained from Korea compared to the United States. Am J Gastroenterol 91:1322-1325, 1996

    PubMed  Google Scholar 

  34. Shimoyama T, Fukuda S, Tanaka M, Mikami T, Saito Y, Munakata A: High prevalence of the CagA-positive Helicobacter pylori strains in Japanese asymptomatic patients and gastric cancer patients. Scand J Gastroenterol 32:465-468, 1997

    PubMed  Google Scholar 

  35. Censini S, Lange C, Xiang Z, Crabtree JE, Ghiara P, Borodovsky M, Rappuoli R, Covacci A: cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc Natl Acad Sci USA 93:14648-14653, 1996

    PubMed  Google Scholar 

  36. Yamaoka Y, Kita M, Kodama T, Sawai N, Imanishi J: Helicobacter pylori cagA gene and expression of cytokine messenger RNA in gastric mucosa. Gastroenterology 110:1744-1752, 1996

    PubMed  Google Scholar 

  37. Maeda S, Yoshida H, Ikenoue T, Ogura K, Kanai F, Kato N, Shiratori Y, Omata M: Structure of cag pathogenicity island in Japanese Helicobacter pylori isolates. Gut 44:336-341, 1999

    PubMed  Google Scholar 

  38. Rachmilewitz D, Karmeli F, Eliakim R, Stalnikowicz R, Ackerman Z, Amir G, Stamler JS: Enhanced gastric nitric oxide synthase activity in duodenal ulcer patients. Gut 35:1394-1397, 1994

    PubMed  Google Scholar 

  39. Shapiro KB, Hotchkiss JH: Induction of nitric oxide synthesis in murine macrophages by Helicobacter pylori. Cancer Lett 102:49-56, 1996

    PubMed  Google Scholar 

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  1. Unit of Endogenous Cancer Risk Factors, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372, Lyon Cedex 08, France

    Chun-Qi Li, Brigitte Pignatelli & Hiroshi Ohshima

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  1. Chun-Qi Li
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  2. Brigitte Pignatelli
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  3. Hiroshi Ohshima
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Li, CQ., Pignatelli, B. & Ohshima, H. Coexpression of Interleukin-8 and Inducible Nitric Oxide Synthase in Gastric Mucosa Infected with cagA+ Helicobacter pylori. Dig Dis Sci 45, 55–62 (2000). https://doi.org/10.1023/A:1005453125433

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