Abstract
Purpose
Helicobacter pylori (H. pylori) is considered to be a major factor contributing to gastric mucosal damage by stimulating mucosal macrophage production of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), but the inflammatory responses within the gastric mucosa in vivo are not well known. Therefore, this study was designed to investigate the expression of TNF-α induced by H. pylori infection which is involved in the tumor initiation and promotion of gastric carcinogenesis.
Methods
This study was carried out in 200 patients, consisting of normal gastric mucosa (n = 20), mucosa with chronic gastritis (n = 63), intestinal metaplasia (n = 20), dysplasia (n = 11), and gastric adenocarcinoma (n = 86), in which the H. pylori status has been analyzed. The expression of TNF-α was studied at mRNA as well as protein level using RT-PCR and western blotting, respectively. The localization of TNF-α was also studied semiquantitatively by immunohistochemistry.
Results
The RT-PCR and western blotting results of TNF-α mRNA and protein expressions were significantly increased in chronic gastritis, intestinal metaplasia, dysplasia and gastric adenocarcinoma patients, respectively. Immunohistochemical study also showed the increased expression of TNF-α in the similar way.
Conclusion
Over expression of TNF-α showed a significant severity-dose–response as risk markers from preneoplastic lesions to gastric cancer.
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References
Ando T, Kusugami K, Ohsuga M, Ina K, Shinoda M, Konagaya T, Sakai T, Imada A, Kasuga N, Nada T, Ichiyama S, Blaser MJ (1998) Differential normalization of mucosal interleukin-8 and interleukin 6 activity after Helicobacter pylori eradication. Infect Immun 66:4742–4747
Bamford KB, Fan X, Crowe SE, Leary JF, Gourley WK, Luthra GK, Brooks EG, Graham DY, Reyes VE, Ernst PB (1998) Lymphocytes in the human gastric mucosa during Helicobacter pylori have a helper cell 1 phenotype. Gastroenterol 114:482–492
Beales IL, Calam J (1998) Interleukin 1 beta and tumour necrosis factor alpha inhibit acid secretion in cultured rabbit parietal cells by multiple pathways. Gut 42:227–234
Crabtree JE, Shallcross TM, Heately RV, Wyatt JI (1991) Mucosal tumour necrosis factor alpha and interleukin-6 in patients with Helicobacter pylori-associated gastritis. Gut 32:1473–1477
Crabtree JE, Xiang Z, Lindely IJ, Tompkins DS, Rappuoli R, Covacci A (1995) Induction of interleukin-8 secretion from gastric epithelial cells by a cagA negative isogenic mutant of Helicobater pylori. J Clin Pathol 48:967–969
Dixon MF, Genta RM, Yardley JH, Correa P (1996) Classification and grading of gastritis. The updated Sydney system. International workshop on the histopathology of gastritis, Houston 1994. Am J Surg Pathol 20:1161–1181
Erikstein BK, Smeland EB, Blomhoff HK, Funderud S, Prydz K, Lesslauer W, Espevik T (1991) Independent regulation of 55-kDa and 75-kDa tumor necrosis factor receptors during activation of human peripheral blood B lymphocytes. Eur J Immunol 21:1033–1037
Fan XG, Chua A, Fan XJ, Keeling PW (1995) Increased gastric production of interleukin-8 and tumor necrosis factor in patients with Helicobacter pylori infection. Clin Pathol 48:133–136
Garcia-Gonzalez MA, Aisa MAP, Strunk M, Benito R, Piazuelo E, Jiménez P, Sopeña F, Lanas A (2009) Relevance of IL-1 and TNF gene polymorphisms on interleukin-1β and tumor necrosis factor-α gastric mucosal production. Hum Immunol 70:935–945
Harris PR, Mobley HL, Perez-Perez GI, Blaser MJ, Smith PD (1996) Helicobacter pylori urease is a potent stimulus of mononuclear phagocyte activation and inflammatory cytokine production. Gastroenterol 111:419–425
Hatz RA, Rieder G, Stolte M, Bayerdorffer E, Meimarakis G, Schildberg FW, Enders G (1997) Pattern of adhesion molecule expression on vascular endothelium in Helicobacter pylori-associated antral gastritis. Gastroenterol 112:1908–1919
Hazell SL, Lee A, Brady L, Hennessy W (1986) Campylobacter pyloridis and gastritis: association with intercellular spaces and adaptation to an environment of mucus as important factors in colonization of the gastric epithellium. J Infect Dis 153:658–663
Hazell SL, Evans DJ Jr, Graham DY (1991) Helicobacter pylori catalase. J Gen Microbiol 137:57–61
IARC (1994) Working group on the evaluation of carcinogenic risks to humans. Infection with Helicobacter pylori. In: IARC (ed) IARC monographs on the evaluation of carcinogenic risks to humans, schistosomes, liver flukes and Helicobacter pylori, vol 61. WHO, Geneva, pp 1–241
Israel DA, Salama N, Arnold CN, Moss SF, Ando T, Wirth HP, Tham KT, Camorlinga M, Blaser MJ, Falkow S, Peek RM Jr (2001) Helicobacter pylori strain specific differences in genetic content identified by microarray, influence host inflammatory responses. J Clin Investig 107:611–620
Jones DM, Lessells AM, Eldridge J (1984) Campylobacter like organisms on the gastric mucosa: culture, histological and serological studies. J Clin Pathol 37:1002–1006
Karttunen R, Karttunen T, Ekre HP, MacDonald TT (1995) Interferon gamma and interleukin-4 secreting cells in the gastric antrum in Helicobacter pylori positive and negative gastritis. Gut 36:341–345
Kim JM, Kim JS, Jung HC, Song IS, Kim CY (2000) Apoptosis of human gastric epithelial cells via caspase-3 activation in response to Helicobacter pylori infection: possible involvement of neutrophils through tumor necrosis factor alpha and soluble Fas ligands. Scand J Gastroenterol 35:40–48
Lindholm C, Quiding-Janbrink M, Lonroth H, Hamlet A, Svennerholm AM (1998) Local cytokine response in Helicobacter pylori-infected subjects. Infect Immun 66:5964–5971
Marshall BJ, Barrett LJ, Prakash C, McCallum RW, Guerrant RL (1990) Urea protects Helicobacter (Campylobacter) pylori from the bactericidal effect of acid. Gastroenerol 99:697–702
Moss SF, Legon S, Davies J, Calam J (1994) Cytokine gene expression in Helicobacter pylori-associated antral gastritis. Gut 35:1567–1570
Robert A, Olafsson AS, Lancaster C, Zhang WR (1991) Interleukin-1 is cytoprotective, antisecretory, stimulates PGE2 synthesis by the stomach and retards gastric emptying. Life Sci 48:123–134
Rudi J, Kuck D, Strand S, von Herbay A, Mariani SM, Krammer PH, Galle PR, Stremmel W (1998) Involvement of the CD95 (Apo-1/Fas) receptor and ligand system in Helicobacter pylori induced gastric epithelial apoptosis. J Clin Investig 102:1506–1514
Suganuma M, Okabe S, Marino MW, Sakai A, Sueoka E, Fujiki H (1999) Essential role of tumor necrosis factor alpha (TNF-alpha) in tumor promotion as revealed by TNF-alpha-deficient mice. Cancer Res 59:4516–4518
Suganuma M, Kuruesu M, Okabe S, Sueoka N, Yoshida M, Wakatsuki Y, Fujiki H (2001) Helicobacter pylori membrane protein 1: a new carcinogenic factor of Helicobacter pylori. Cancer Res 61:6356–6359
Suganuma M, Kurusu M, Suzuki K, Nishizono A, Murakami K, Fujioka T, Fujiki H (2005) New tumor necrosis factor-alpha-inducing protein released from Helicobacter pylori for gastric cancer progression. J Cancer Res Clin Oncol 131:305–313
Suganuma M, Kuzuhara T, Yamaguchi K, Fujiki H (2006) Carcinogenic role of tumor necrosis factor-alpha inducing protein of Helicobacter pylori in human stomach. J Biochem Mol Biol 39:1–8
Suganuma M, Yamaguchi K, Ono Y, Matsumoto H, Hayashi T, Ogawa T, Imai K, Kuzuhara T, Nishizono A, Fujiki H (2008) TNF-alpha-inducing protein, a carcinogenic factor secreted from Helicobacter pylori, enters gastric cancer cells. Int J Cancer 123:117–122
Takagi A, Watanabe S, Igarashi M, Koike J, Hasumi K, Deguchi R, Koga Y, Miwa T (2000) The effect of Helicobacter pylori on cell proliferation and apoptosis in gastric epithelial cell lines. Aliment Pharmacol Ther 14:188–192
Talmadge JE, Phillips H, Schneider M, Rowe T, Pennington R, Bowersox O, Lenz B (1998) Immunomodulatory properties of recombinant murine and human tumor necrosis factor. Cancer Res 48:544–550
Wagner S, Beil W, Westermann J, Logan RP, Bock CT, Trautwein C, Bleck JS, Manns MP (1997) Regulation of epithelial cell growth by Helicobacter pylori: offdence for a major role of apoptosis. Gastroenterol 113:1836–1847
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Senthilkumar, C., Niranjali, S., Jayanthi, V. et al. Molecular and histological evaluation of tumor necrosis factor-alpha expression in Helicobacter pylori-mediated gastric carcinogenesis. J Cancer Res Clin Oncol 137, 577–583 (2011). https://doi.org/10.1007/s00432-010-0921-9
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DOI: https://doi.org/10.1007/s00432-010-0921-9