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Induction of cyclooxygenase-2 overexpression in human gastric epithelial cells by Helicobacter pylori involves TLR2/TLR9 and c-Src-dependent nuclear factor-kappaB activation.
Mol Pharmacol 2004; 66(6):1465-77MP

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)-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 Tyr188 and Tyr199 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.

Authors+Show Affiliations

Department of Pharmacology, College of Medicine, National Taiwan University and National Taiwan University Hospital, Taipei, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15456896

Citation

Chang, Ya Jen, et al. "Induction of Cyclooxygenase-2 Overexpression in Human Gastric Epithelial Cells By Helicobacter Pylori Involves TLR2/TLR9 and c-Src-dependent Nuclear factor-kappaB Activation." Molecular Pharmacology, vol. 66, no. 6, 2004, pp. 1465-77.
Chang YJ, Wu MS, Lin JT, et al. Induction of cyclooxygenase-2 overexpression in human gastric epithelial cells by Helicobacter pylori involves TLR2/TLR9 and c-Src-dependent nuclear factor-kappaB activation. Mol Pharmacol. 2004;66(6):1465-77.
Chang, Y. J., Wu, M. S., Lin, J. T., Sheu, B. S., Muta, T., Inoue, H., & Chen, C. C. (2004). Induction of cyclooxygenase-2 overexpression in human gastric epithelial cells by Helicobacter pylori involves TLR2/TLR9 and c-Src-dependent nuclear factor-kappaB activation. Molecular Pharmacology, 66(6), pp. 1465-77.
Chang YJ, et al. Induction of Cyclooxygenase-2 Overexpression in Human Gastric Epithelial Cells By Helicobacter Pylori Involves TLR2/TLR9 and c-Src-dependent Nuclear factor-kappaB Activation. Mol Pharmacol. 2004;66(6):1465-77. PubMed PMID: 15456896.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Induction of cyclooxygenase-2 overexpression in human gastric epithelial cells by Helicobacter pylori involves TLR2/TLR9 and c-Src-dependent nuclear factor-kappaB activation. AU - Chang,Ya Jen, AU - Wu,Ming Shiang, AU - Lin,Jaw Town, AU - Sheu,Bor Shyang, AU - Muta,Tatsushi, AU - Inoue,Hiroyasu, AU - Chen,Ching-Chow, Y1 - 2004/09/29/ PY - 2004/10/1/pubmed PY - 2005/3/25/medline PY - 2004/10/1/entrez SP - 1465 EP - 77 JF - Molecular pharmacology JO - Mol. Pharmacol. VL - 66 IS - 6 N2 - 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 Tyr188 and Tyr199 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. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/15456896/Induction_of_cyclooxygenase_2_overexpression_in_human_gastric_epithelial_cells_by_Helicobacter_pylori_involves_TLR2/TLR9_and_c_Src_dependent_nuclear_factor_kappaB_activation_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15456896 DB - PRIME DP - Unbound Medicine ER -