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OBJECTIVE To verify the antiulcer activity of antidepressant duloxetine, and explore the antiulcer mechanism in the regulation of immunoregulatory network.METHODS We used pathological section with hematoxylin eosin (HE) staining to observe the protective effect of duloxetine on stress gastric ulcer in rats.We used the blood cell counter to detect the numbers of inflammatory cells in the rat whole blood, and used cytokine antibody microarray to detect the inflammatory cytokines in gastric mucosal.RESULTS ① With stress time lasting (from 15 min to 6 h), injury and bleeding of rat gastric mucosa were gradually increasing.In microscopic, mucosa and gland loss, inflammatory cells infiltration and crater-like ulcers were observed in stress rat gastric mucosa.Duloxetine can effectively reverse these mucosal damage induced by water immersion restraint stress 6 h, and maintain the structural integrity of gastric mucosa.② Compared with vehicle control, the white blood cells, lymphocytes and intermediate cells in whole blood significantly increased after stress 6 h in rats, while the plateletcrit, mean platelet volume, platelet distribution width, hematocrit, red blood cell volume distribution width had no significant changes.Duloxetine can significantly reverse the increase of inflammatory cells caused by stress 6 h.③ Cytokine antibody array results showed that stress 6 h significantly increased the expression of Thymus Chemokine-1, CINC-2α, CINC-3 and Fas Ligand in gastric mucosa, and duloxetine can effectively reverse the increase caused by stress.Expression of ICAM-1, L-Selectin and Prolactin R significantly reduced in stress rat, and duloxetine can effectively reverse the decrease caused by stress.CONCLUSION Duloxetine effectively reversed these mucosal damage induced by water immersion restraint stress 6 h, and maintained the structural integrity of gastric mucosa, this identified its potential gastric protective effect.Duloxetine lightened the local gastric inflammation by inhibiting gastric mucosa cells apoptosis through the reduction of Fas Ligand and inhibiting the recruitment of inflammatory cells through the reduction of chemotactic cytokines in the gastric mucosa, and reduced the inflammatory reaction through partly reversing the increase of inflammatory cells induced by stress.It performed protective effect on stress induced gastric ulcer may through the regulation of immunoregulatory network.All these results provided evidences for the antiulcer activity of antidepressants and suggested some clues for the development of new antiulcer drugs.