Intestinal trefoil factor (ITF or TFF3), NO and epitheliumassociated mucin have important roles in sustaining mucosal integrity in the gastrointestinal tract. In the present study we examined ITF-binding molecules on IEC-18 cells (an intestinal epithelial cell line) with the use of flow cytometry and localized these molecules on the cell surface by confocal microscopy. Furthermore, we studied the interaction of mucin and ITF and their co-operative effect on NO production by the epithelium.
Trefoil factors are small peptides found in several mammalian tissues including gut, respiratory tract and brain. Their physiological function is not well understood. Among them, trefoil factor 3 (intestinal trefoil factor) is known to be cytoprotective in the gut. However, the molecular mechanism and secondary mediators of trefoil factor 3 action are not known. In the present study, we examined whether the cyclooxygenase pathway is involved in trefoil factor 3 action. We showed that trefoil factor 3 significantly induces the production of prostaglandin E(2) and prostaglandin I(2) in IEC-18 cells (an intestinal epithelial cell line) in a dose dependent manner. Western blot and immunohistochemistry revealed that trefoil factor 3 (2.5 microM) up-regulates the expression of cyclooxygenase-2 but not cyclooxygenase-1 in IEC-18 cells. Treating cells with trefoil factor 3 (10 microM) significantly attenuated reactive oxygen species-induced IEC-18 cell injury. This effect is blocked by NS-398 (10 microM), a selective cyclooxygenase-2 inhibitor. Moreover, we demonstrated that exogenously administered carbacyclin (1 microM, a stable analogue of prostaglandin I(2)) and/or prostaglandin E(2) (1 microM) caused a significant reduction of reactive oxygen species-induced cell injury, mimicking the effect of trefoil factor 3. In summary, our results indicate that trefoil factor 3 activates cyclooxygenase-2 in intestinal epithelium to produce prostaglandin I(2) and prostaglandin E(2), which function as survival factors and mediate the cytoprotective action of trefoil factor 3 against oxidant injury.
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