PPARγ mediates NSAIDs‐induced upregulation of TFF2 expression in gastric epithelial cells

Abstract

Trefoil factor family (TFF) is a group of peptides that play critical roles in maintaining gastric mucosal integrity. In real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) and reporter gene assays, we show that indomethacin and aspirin upregulate TFF2 expression in MKN45 gastric cells. These drugs also activated peroxisome proliferator-activated receptor Q Q (PPARQ Q) at concentration ranges that increase TFF2 expression, and upregulated TFF2 expression was suppressed by GW9662, a speci¢c inhibitor of PPARQ Q. These results suggest that indomethacin and aspirin upregulate gastric expression of TFF2 through activation of PPARQ Q. This mechanism may be important in reducing the extent of gastric mucosal injury caused by the administration of non-steroidal anti-in£ammatory drugs (NSAIDs).

Trefoil factors: Gastrointestinal-specific proteins associated with gastric cancer

“…Regulation of TFF2 by gastrin may play a role in the protection and repair of the gastrointestinal mucosa [35]. Besides, although non-steroidal anti-inflammatory drugs (NSAIDs) has no notable effect on the expression of TFF1 and TFF3 mRNA, it upregulates TFF2 mRNA expression through activation of peroxisome proliferator-activated receptor γ (PPAR γ) in a dose-and time-dependent manner [88,89] (Table 2). This mechanism may be important in reducing the extent of gastric mucosal damage caused by the administration of NSAIDs [89].…”

“…Besides, although non-steroidal anti-inflammatory drugs (NSAIDs) has no notable effect on the expression of TFF1 and TFF3 mRNA, it upregulates TFF2 mRNA expression through activation of peroxisome proliferator-activated receptor γ (PPAR γ) in a dose-and time-dependent manner [88,89] (Table 2). This mechanism may be important in reducing the extent of gastric mucosal damage caused by the administration of NSAIDs [89]. In addition, after treating with prebiotic galacto-oligosaccharides (GOS), the expressions of MUC2 and TFF3 are significantly up-regulated (Table 2), which indicates that GOS may enhance mucosal protective function via direct stimulation of intestinal goblet cells [90].…”

Trefoil factors

“…Both prostaglandins and trefoil peptides have cytoprotective functions in the gastric mucosa [44,45], and it has been suggested that the actions of these two families may be linked [46]. A common linkage may be one or more members of the prostaglandin and peroxisome proliferator-activated receptors (PPARs) transcription factor family of nuclear receptors, which are involved in modulating cell growth, differentiation and infl ammation in the gut and elsewhere [47,48].…”

“…A common linkage may be one or more members of the prostaglandin and peroxisome proliferator-activated receptors (PPARs) transcription factor family of nuclear receptors, which are involved in modulating cell growth, differentiation and infl ammation in the gut and elsewhere [47,48]. The PPARg receptor in particular has been shown to be expressed by the normal gastric mucosa, and gastric cancer cell lines, and the PPARg ligands 15d-PGJ 2 and troglitazone (TGZ), act to suppress DNA synthesis in these cells and also upregulate both TFF1 and TFF2 mRNA in a dose-dependent fashion [46,49]. Evidence has been presented that the previously observed stimulatory effects of non-steroidal anti-infl ammatory drugs (NSAIDs) on TFF2 gene transcription in cell lines [50,51] may be mediated by a direct effect of these drugs on PPARg, since both indomethacin and aspirin stimulate PPAR-luc transcription, which can be blocked by the PPARg inhibitor GW9662 [46].…”

“…The PPARg receptor in particular has been shown to be expressed by the normal gastric mucosa, and gastric cancer cell lines, and the PPARg ligands 15d-PGJ 2 and troglitazone (TGZ), act to suppress DNA synthesis in these cells and also upregulate both TFF1 and TFF2 mRNA in a dose-dependent fashion [46,49]. Evidence has been presented that the previously observed stimulatory effects of non-steroidal anti-infl ammatory drugs (NSAIDs) on TFF2 gene transcription in cell lines [50,51] may be mediated by a direct effect of these drugs on PPARg, since both indomethacin and aspirin stimulate PPAR-luc transcription, which can be blocked by the PPARg inhibitor GW9662 [46]. However, the in vivo actions of NSAIDs may be more complex, since it has been shown that acute and chronic dosing of aspirin in rats altered neither TFF1 nor TFF2 mRNA, nor protein expression [52].…”