Tumor Necrosis Factor-Alpha Acts Reciprocally With Solute Carrier Family 26, Member 3, (Downregulated-In-Adenoma) And Reduces Its Expression, Leading To Intestinal Inflammation

Solute carrier family 26, member 3 (Slc26a3), also termed downregulated-in-adenoma (DRA) is a member of the Slc26 family of anion transporters and is mutated in congenital chloride diarrhea. Our previous study demonstrated that DRA deficiency is associated with severely reduced colonic HCO3- secretion, a loss of colonic fluid absorption, a lack of a firmly adherent mucus layer and a severely reduced colonic mucosal resistance to dextran sodium sulfate (DSS) damage. However, the direct effect of mediators that trigger intestinal inflammatory factors on DRA has not been fully investigated. Tumor necrosis factor (TNF)-alpha is a central mediator of intestinal inflammation in inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease. However, to the best of our knowledge, whether TNF-alpha acts reciprocally with DRA leading to the development of gut inflammation in IBD has not been reported. The present study identified that the expression level of DRA was reduced in active UC patients and DSS-induced colitis mice with high expression levels of TNF-alpha identified in the peripheral blood serum. In addition, TNF-alpha may affect the expression level of DRA in human colonic Caco2BBE cells in a dose-dependent manner, including in DRA overexpressed Caco2BBE cells. Furthermore, knockdown of TNF-alpha in Caco2BBE cells led to a higher expression level of DRA and a markedly reduced secretion of TNF-alpha in the culture media. In addition, knockdown of DRA in Caco2BBE cells led to a higher secretion of TNF-alpha in the culture media compared with the control cells, which could be reversed by overexpression of DRA. Overall, these results indicate that TNF-alpha may act reciprocally with DRA, leading to the development of intestinal inflammation. Based on the pivotal position of TNF-alpha in IBD, DRA is hypothesized to have therapeutic potential against colitis serving as an important target.