Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-27472
Toller, I M; Hitzler, I; Sayi, A; Mueller, A (2010). Prostaglandin E2 prevents Helicobacter-induced gastric preneoplasia and facilitates persistent infection in a mouse model. Gastroenterology, 138(4):1455-1467.e4 .
BACKGROUND AND AIMS:: Persistent infection with the human pathogen Helicobacter pylori increases the risk of gastric cancer. In this study, we investigated the role of cyclooxygenase-2 (COX-2) and its main product, prostaglandin E(2) (PGE(2)), in the development of Helicobacter-induced gastritis and gastric cancer precursor lesions. METHODS:: We utilized mouse models of Helicobacter-induced gastric preneoplasia and vaccine-induced protection to study the effects of COX-2 inhibition and PGE(2) treatment on the induction of Helicobacter-specific immune responses and gastric premalignant immunopathology. RESULTS:: COX-2 and PGE(2) are up-regulated upon Helicobacter infection in cultured epithelial cells and in the gastric mucosa of infected mice. Inhibition of COX-2 activity with Celecoxib significantly accelerated early preneoplasia; conversely, systemic administration of synthetic PGE(2) prevented the development of premalignant pathology and completely reversed pre-existing lesions by suppressing IFN-gamma production in the infected stomachs. The protective effect of PGE(2) was accompanied by increased Helicobacter colonization in all models. All in vivo effects were attributed to immunosuppressive effects of PGE(2) on CD4(+) T-helper 1 (Th1) cells, which fail to migrate, proliferate and secrete cytokines when exposed to PGE(2)in vitro and in vivo. T-cell inhibition was found to be due to silencing of IL-2 gene transcription, and could be overcome by supplementation with recombinant IL-2 in vitro and in vivo. CONCLUSIONS:: COX-2-dependent production of PGE(2) has an important immunomodulatory role during Helicobacter infection, preventing excessive local immune responses and the associated immunopathology by inhibiting the effector functions of pathogenic Th1 cells.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Institute of Molecular Cancer Research|
07 Faculty of Science > Institute of Molecular Cancer Research
08 University Research Priority Programs > Systems Biology / Functional Genomics
|DDC:||570 Life sciences; biology|
|Deposited On:||23 Jan 2010 20:07|
|Last Modified:||27 Nov 2013 18:28|
|Citations:||Web of Science®. Times cited: 19|
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