Dexamethasone Upregulates the Expression of the Human SLC26A3 (DRA, Down-Regulated in Adenoma) Transporter (an IBD Susceptibility Gene) in Intestinal Epithelial Cells and Attenuates Gut Inflammation.

BACKGROUND

Down-Regulated in Adenoma (DRA) plays a critical role in intestinal chloride absorption and a decrease in its expression is a key event in diarrheal disorders. Recently, DRA has emerged as an Inflammatory Bowel Disease (IBD) susceptibility gene. Therefore, the strategies to upregulate DRA expression are potentially novel approaches to not only treat IBD-associated diarrhea but also gut inflammation. In this study, the effect of dexamethasone (DEX), an anti-inflammatory corticosteroid on DRA expression was investigated.

METHODS

GR (glucocorticoid receptor) overexpressed Caco-2 cells and C57BL/6/J mice and anti-αIL-10R mAb model of IBD were used. Protein expression was assessed by immunoblotting and immunofluorescence. Transcript levels were assessed by quantative-real-time polymerase chain reaction (qRT-PCR) and promoter activity was measured by luciferase assays.

RESULTS

Our results showed that DEX significantly increased DRA mRNA and protein expression in GR overexpressing Caco-2 cells. DEX-induced upregulation of DRA was GR dependent and appeared at least in part to occur via a transcriptional mechanism, as promoter activity of the DRA construct (-1183/+114 bp) was significantly increased in response to DEX. The increase in DRA mRNA was abrogated in the presence of MKP-1 inhibitor, triptolide. Administration of DEX (2 mg/kg body weight) to mice for 24 and 48 hours significantly increased the DRA expression in mouse colon. DEX treatment to mice for 7 days in the αIL-10R mAb model of colitis was able to significantly attenuate the gut inflammation and associated decrease in DRA expression.

CONCLUSIONS

We demonstrate that DEX stimulates DRA expression via transcriptional mechanisms and suggest that upregulation of DRA may contribute to both anti-inflammatory and pro-absorptive effects of DEX.