Prostaglandin E2 prevents Helicobacter-induced gastric preneoplasia and facilitates persistent infection in a mouse model.
OBJECTIVE
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 PGE(2) 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.
Toller
Isabella M
IM
Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland.
Hitzler
Iris
I
Sayi
Ayca
A
Mueller
Anne
A
D000818:Animals; D051546:Cyclooxygenase 2 / Q000502:physiology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005753:Gastric Mucosa / Q000473:pathology; D016481:Helicobacter Infections / Q000150:complications* / Q000276:immunology / Q000473:pathology; D016753:Interleukin-10 / Q000502:physiology; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011230:Precancerous Conditions / Q000517:prevention & control*; D013274:Stomach Neoplasms / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D052246:Cyclooxygenase 2 Inhibitors; D007376:Interleukin-2; D016753:Interleukin-10; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone