IFN-gamma downregulates expression of Na+/H+ exchangers NHE2 and NHE3 in rat intestine and human Caco-2/bbe cells

Diarrhea associated with inflammatory bowel diseases has traditionally been attributed to stimulated secretion. The purpose of this study was to deter mine whether chronic stimulation of intestinal mucosa by interferon-gamma ( IFN-gamma) affects expression and function of the apical membrane Na+/H+ ex changers NHE2 and NHE3 in rat intestine and Caco-2/bbe (C2) cells. Confluen t C2 cells expressing NHE2 and NHE3 were treated with IFN-gamma for 2, 24, and 48 h. Adult rats were injected with IFN-gamma intraperitoneally for 12 and 48 h. NHE2 and NHE3 activities were measured by unidirectional Na-22 in flux across C2 cells and in rat brush-border membrane vesicles. NHE protein and mRNA were assessed by Western and Northern blotting. IFN-gamma treatme nt of C2 monolayers caused a >50% reduction in NHE2 and NHE3 activities and protein expression. In rats, region-specific, time- and dose-dependent red uctions of NHE2 and NHE3 activities, protein expression, and mRNA were obse rved after exposure to IFN-gamma. Chronic exposure of intestinal epithelial cells to IFN-gamma results in selective downregulation of NHE2 and NHE3 ex pression and activity, a potential cause of inflammation-associated diarrhe a.