Neutrophil infiltration mediated by tumor necrosis factor- (TNF-) is associated with various types of gastric injury, whereas prostaglandins (PGs) play a crucial role in gastric defense. We examined the roles of two isoforms of cyclooxygenase (COX) and PGE₂ in Helicobacter pylori (H. pylori)-induced gastritis in mice. Mice infected with H. pylori were given SC-560 (selective COX-1 inhibitor: 10 mg/kg), NS-398 (selective COX-2 inhibitor: 10 mg/kg), or indomethacin (nonselective COX inhibitor: 2 mg/kg) with or without 16, 16-dimethyl PGE₂ for one week. H. pylori infection increased levels of mRNA for COX-1 and COX-2 in gastric tissue by 1.2-fold and 3.3-fold, respectively, accompanied by a significant increase in PGE₂ production by gastric tissue. H. pylori infection significantly elevated myeloperoxidase (MPO) activity, a marker of neutrophil infiltration, and epithelial cell apoptosis in the stomach. SC-560 augmented MPO activity and epithelial cell apoptosis with an associated reduction in PGE₂ production, while NS-398 had the same effects without affecting PGE₂ production. Inhibition of both COX-1 and COX-2 by indomethacin or concurrent treatment with SC-560 and NS-398 resulted in a stronger increase in MPO activity and apoptosis than inhibition of either COX-1 or COX-2 alone. H. pylori infection elevated TNF- mRNA expression in the stomach, which was further increased by indomethacin. The effects of COX inhibitors on neutrophil infiltration, apoptosis, and TNF- expression in H. pylori-infected mice were abolished by exogenous 16, 16-dimethyl PGE₂. In conclusion, PGE₂ derived from either COX-1 or COX-2 is involved in the regulation of gastric mucosal inflammation and contributes to maintenance of mucosal integrity during H. pylori infection via inhibition of TNF- expression.