Prostaglandin E2 Prevents Helicobacter-Induced Gastric Preneoplasia and Facilitates Persistent Infection in a Mouse Model


Toller I. M., Hitzler I., Sayi A., Mueller A.

GASTROENTEROLOGY, vol.138, no.4, pp.1455-1471, 2010 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 138 Issue: 4
  • Publication Date: 2010
  • Doi Number: 10.1053/j.gastro.2009.12.006
  • Journal Name: GASTROENTEROLOGY
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.1455-1471
  • Keywords: Helicobacter pylori, Gastric Cancer, Cyclooxygenase, Prostaglandin E-2, PYLORI-INDUCED GASTRITIS, T-CELL, COLORECTAL-CANCER, MONGOLIAN GERBILS, CYCLOOXYGENASE-2, MICE, RISK, DISRUPTION, EXPRESSION, CARCINOMA
  • Istanbul Technical University Affiliated: Yes

Abstract

BACKGROUND & 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 development of premalignant pathology and completely reversed preexisting lesions by suppressing interferon-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 cells, which fail to migrate, proliferate, and secrete cytokines when exposed to PGE2 in vitro and in vivo. T-cell inhibition was found to be due to silencing of interleukin-2 gene transcription, and could be overcome by supplementation with recombinant interleukin-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 T-helper 1 cells.