Induction of cyclooxygenase-2 overexpression in human gastric epithelial cells by Helicobacter pylori involves TLR2/TLR9 and c-Src-dependent nuclear factor-κB activation

被引:112
作者
Chang, YJ
Wu, MS
Lin, JT
Sheu, BS
Muta, T
Inoue, H
Chen, CC
机构
[1] Natl Taiwan Univ, Coll Med, Dept Pharmacol, Taipei 10018, Taiwan
[2] Natl Taiwan Univ, Coll Med, Dept Internal Med, Div Gastroenterol, Taipei 10018, Taiwan
[3] Natl Taiwan Univ Hosp, Taipei, Taiwan
[4] Natl Cheng Kung Univ, Coll Med, Dept Internal Med, Tainan 70101, Taiwan
[5] Kyushu Univ, Grad Sch Med Sci, Dept Mol & Cellular Biochem, Fukuoka 812, Japan
[6] Natl Cardiovasc Ctr, Res Inst, Dept Pharmacol, Osaka, Japan
关键词
D O I
10.1124/mol.104.005199
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Gastric epithelial cells were incubated with a panel of clinical isolates of Helicobacter pylori, including nonulcer dyspepsia with gastritis (HS, n=20), gastric ulcer (HU, n=20), duodenal ulcer (HD, n=21), and gastric cancer (HC, n=20). HC strains induced a higher cyclooxygenase-2 (COX-2) expression than those from HS, HD, and HU. The bacterial virulence factors and the host cellular pathways were investigated. Virulence genes of iceA, vacA, babA2, cagA 3' repeat region, and hrgA failed to show any association with the disease status and COX-2 expression. Methylation-specific polymerase chain reaction revealed HC strains not affecting the methylation status of COX-2 promoter. Nuclear factor (NF)-kappaB, NF-interleukin 6, and cAMP response element were found to be involved in COX-2 induction. We explored a novel NF-kappaB activation pathway. The mutants of TLR2 and TLR9, but not TLR4, inhibited H. pylori-induced COX-2 promoter activity, and neutralizing antibodies for TLR2 and TLR9 abolished H. pylori-induced COX-2 expression. Phosphatidylinositol-specific phospholipase C (PI-PLC), protein kinase C (PKC), and Src inhibitors inhibited COX-2 induction. The dominant-negative mutants of NIK and various IkappaB kinase complexes, including IKKbeta (Y188F), IKKbeta (Y199F), and IKKbeta (FF), inhibited the COX-2 promoter activity. Phosphorylation of GST-IKKbeta (132-206) at Tyr(188) and Tyr(199) by c-Src was found after H. pylori infection. In summary, H. pylori induces COX-2 expression via activations of NF-kappaB, NF-interleukin 6, the cAMP response element. In NF-kappaB activation, H. pylori acts through TLR2/TLR9 to activate both the cascade of PI-PLCgamma/PKCalpha/c-Src/IKKalpha/beta and the cascade of NIK/IKKalpha/beta, resulting in the IkappaBalpha degradation and the expression of COX-2 gene. The COX-2 overexpression may contribute to the carcinogenesis in patients colonized with these strains.
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收藏
页码:1465 / 1477
页数:13
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