Molecular biological study on the expression and functions of trefoil factor family(TFF) peptides in gastrointestinal mucosa

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Trefoil factor family(TFF) is a group of protease resistant peptides mainly expressed in gastrointestinal epithelial cells. To date, three TFF peptides are identified in humans, TFF1 (pS2), TFF2 (SP), and TFF3 (LTF). It is well established that TFF peptides play critical roles in the defense and repair of gastrointestinal mucosa. In this study, in order to understand the regulatory mechanisms of TFF expression, we examined the effects of growth factors, cytokines, ligands for various nuclear receptors, and NSAIDs on the expression of TFF in primazy cultured gastrointestinal mucosal cells as well as in cell lines derived from gastrointestinal epithelial cells. Endogenous TFF mRNA expression was analyzed by real-time quantitative RT-PCR and reporter gene assays were also performed. Major findings are as follows : (1)TFF1 was originally discovered as an estrogen-inducible gene in MCF-7 bieast cancer cells. Although we identified the expression of estrogen receptors(ER)(mainly ERβ) in gastric epithelial cells, 17β-estradiol had no significant effect on the expression of endogenous TFF1 mRNA as well as the transcription of TFF1 reporter genes, suggesting that gastric expression of TFF1 is independent of ER. (2)TNFα and phorbol ester up-regulated TFF1 expression. Reporter gene assay showed that NF-κB and AP-1 mediates the action of TNF-α and phorbol ester, respectively. (3)Ligands for PPARγ, such as troglitazone and 15d-PGJ2, were found to up-regulate TFF2 expression in gastric epithelial cells. We identified the presence of a functional peroxisome proliferator responsive element(PPRE) within the promoter region of human TFF2 gene. (4)We also found that NSAIDs, such as indomethacin and aspirin, up-regulates TFF2 expression through activating PPARγ. Since TFF2 is a critical cytoprotective agent, this mechanism may reduce the degree of gastric mucosal damage induced by these NSAIDs.