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

Ya Jen Chang, Ming Shiang Wu, Jaw Town Lin, Bor Shyang Sheu, Tatsushi Muta, Hiroyasu Inoue, Ching Chow Chen

Research output: Contribution to journalArticlepeer-review

111 Citations (Scopus)

Abstract

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)-κB, NF-interleukin 6, and cAMP response element were found to be involved in COX-2 induction. We explored a novel NF-κB 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 IκB kinase complexes, including IKKβ (Y188F), IKKβ (Y199F), and IKKβ (FF), inhibited the COX-2 promoter activity. Phosphorylation of GST-IKKβ (132-206) at Tyr188 and Tyr199 by c-Src was found after H. pylori infection. In summary, H. pylori induces COX-2 expression via activations of NF-κB, NF-interleukin 6, the cAMP response element. In NF-κB activation, H. pylori acts through TLR2/TLR9 to activate both the cascade of PI-PLCγ/PKCα/c-Src/IKKα/β and the cascade of NIK/IKKα/β, resulting in the IκBα degradation and the expression of COX-2 gene. The COX-2 overexpression may contribute to the carcinogenesis in patients colonized with these strains.

Original languageEnglish
Pages (from-to)1465-1477
Number of pages13
JournalMolecular pharmacology
Volume66
Issue number6
DOIs
Publication statusPublished - 2004 Dec

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Fingerprint

Dive into the research topics of 'Induction of cyclooxygenase-2 overexpression in human gastric epithelial cells by Helicobacter pylori involves TLR2/TLR9 and c-Src-dependent nuclear factor-κB activation'. Together they form a unique fingerprint.

Cite this