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

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 E₂ (PGE₂), 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 PGE₂ treatment on the induction of Helicobacter-specific immune responses and gastric premalignant immunopathology. Results: COX-2 and PGE₂ 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 PGE₂ prevented development of premalignant pathology and completely reversed preexisting lesions by suppressing interferon-γ production in the infected stomachs. The protective effect of PGE₂ was accompanied by increased Helicobacter colonization in all models. All in vivo effects were attributed to immunosuppressive effects of PGE₂ 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 PGE₂ 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.