Helicobacter pylori-induced invasion and angiogenesis of gastric cells is mediated by cyclooxygenase-2 induction through TLR2/TLR9 and promoter regulation
Journal
Journal of Immunology
Journal Volume
175
Journal Issue
12
Pages
8242-8252
Date Issued
2005
Author(s)
Abstract
Cyclooxygenase-2 (COX-2) plays a crucial role in Helicobacter pylori-associated gastric cancer. In this study, we report that H. pylori-induced COX-2 expression enhances the cancer cell invasion and angiogenesis via TLR2 and TLR9, which can be attenuated by the specific COX-2 inhibitor NS398 or celecoxib. The cAMP response element (CRE) and API sites, but not κB on the COX-2 promoter, are involved in MAPKs-regulated COX-2 expression. Differential bindings of the CREB-1, ATF-2, c-jun to the CRE site, and the c-fos, c-jun, ATF-2 to the AP1 site are demonstrated by DNA affinity protein-binding, supershift, and chromatin immunoprecipitation assays. Activations of these transcription factors were attenuated by different MAPKs inhibitors. The mutants of TLR2, TLR9, or MAPKs inhibited H. pyloi-induced COX-2 promoter, CRE, and AP-1 activities. MAPKs inhibitors attenuated the H. pylori-induced COX-2 mRNA and protein expressions. These results indicate that H. pylori acts through TLR2 and TLR9 to activate MAPKs, especially p38, and their downstream transcription factors (CREB-1, ATF-2, c-jun, and c-fos), resulting in the activations of CRE and AP-1 on the COX-2 promoter. These intracellular networks drive the COX-2-dependent PGE2 release and contribute to cell invasion and angiogenesis. Copyright ? 2005 by The American Association of Immunologists, Inc.
SDGs
Other Subjects
activating transcription factor 2; celecoxib; cyclooxygenase 2; cyclooxygenase 2 inhibitor; DNA; I kappa B; messenger RNA; mitogen activated protein kinase; mitogen activated protein kinase inhibitor; mitogen activated protein kinase p38; n (2 cyclohexyloxy 4 nitrophenyl)methanesulfonamide; prostaglandin E2; protein c fos; stress activated protein kinase; toll like receptor 2; toll like receptor 9; transcription factor AP 1; article; assay; binding affinity; cancer invasion; chromatin immunoprecipitation; controlled study; cyclic AMP responsive element; dna affinity protein binding assay; enzyme activation; enzyme activity; enzyme induction; enzyme regulation; Helicobacter pylori; human; human cell; nonhuman; priority journal; promoter region; prostaglandin release; protein binding; protein DNA binding; protein expression; protein function; stomach cancer; stomach carcinogenesis; supershift assay; tumor vascularization
Type
journal article