Prostanoids mediate the protective effect of trefoil factor 3 in oxidant-induced intestinal epithelial cell injury: role of cyclooxygenase-2

Trefoil factors are small peptides found in several mammalian tissues inclu ding gut, respiratory tract and brain. Their physiological function is not well understood. Among them, trefoil factor 3 (intestinal trefoil factor) i s known to be cytoprotective in the gut. However, the molecular mechanism a nd secondary mediators of trefoil factor 3 action are not known. In the pre sent study, we examined whether the cyclooxygenase pathway is involved in t refoil factor 3 action. We showed that trefoil factor 3 significantly induc es the production of prostaglandin E-2 and prostaglandin I-2 in IEC-18 cell s (an intestinal epithelial cell line) in a dose dependent manner. Western blot and immunohistochemistry revealed that trefoil factor 3 (2.5 mu M) up- regulates the expression of cyclooxygenase-2 but not cyclooxygenase-1 in IE C-18 cells, Treating cells with trefoil factor 3 (10 mu M) significantly at tenuated reactive oxygen species-induced IEC-18 cell injury This effect is blocked by NS-398 (10 mu M), a selective cyclooxygenase-2 inhibitor. Moreov er, we demonstrated that exogenously administered carbacyclin (1 mu M, a st able analogue of prostaglandin I-2) and/or prostaglandin E-2 (1 mu M) cause d a significant reduction of reactive oxygen species-induced cell injury, m imicking the effect of trefoil factor 3, In summary, our results indicate t hat trefoil factor 3 activates cyclooxygenase-2 in intestinal epithelium to produce prostaglandin I-2 and prostaglandin E-2, which function as surviva l factors and mediate the cytoprotective action of trefoil factor 3 against oxidant injury.