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 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.
Tan
X D
XD
Department of Pathology, Children's Memorial Hospital, Northwestern University, Chicago, IL 60614, USA. xtan@nwu.edu
Chen
Y H
YH
Liu
Q P
QP
Gonzalez-Crussi
F
F
Liu
X L
XL
D000818:Animals; D002461:Cell Line, Transformed; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000502:physiology*; D011464:Epoprostenol / Q000502:physiology*; D006133:Growth Substances / Q000502:physiology*; D007413:Intestinal Mucosa / Q000473:pathology* / Q000502:physiology*; D007527:Isoenzymes / Q000502:physiology*; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D016877:Oxidants / Q000633:toxicity*; D010455:Peptides / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D051381:Rats; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3
D006133:Growth Substances; D007527:Isoenzymes; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D016877:Oxidants; D010455:Peptides; D017382:Reactive Oxygen Species; C099037:TFF3 protein, rat; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D011464:Epoprostenol; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone