Tumor necrosis factor- (TNF-) is a cytokine produced during gastric mucosal injury. We examined whether TNF- could promote mucosal repair by stimulation of epithelial cell proliferation and explored further the underlying mechanisms in a rat gastric mucosal epithelial cell line (RGM-1). TNF- treatment (1-10 ng/ml) for 12 or 24 hr significantly increased cell proliferation but did not induce apoptosis in RGM-1 cells. TNF- treatment significantly increased cytosolic phospholipase A₂ and cyclooxygenase-2 (COX-2) protein expression, and prostaglandin E₂ (PGE₂) level but did not affect the protein levels of epidermal growth factor, basic fibroblast growth factor and COX-1 in RGM-1 cells. The mRNA of TNF-R2 but not TNF-R1 receptor was also increased. Dexamethasone dose-dependently inhibited the stimulatory effect of TNF- on cell proliferation, which was associated with a significant decrease in cellular COX-2 expression and PGE₂ level. A selective COX-2 inhibitor (DFU) by itself had no effect on basal cell proliferation but significantly reduced the stimulatory effect of TNF- on RMG-1 cells. Combination of dexamethasone and DFU did not produce an additive effect. PGE₂ significantly reversed the depressive action of dexamethasone on cell proliferation. These results suggest that TNF- plays a regulatory role in epithelial cell repair in the gastric mucosa via the TNF- receptor and activation of the arachidonic acid/PG pathway.