IFN-γ 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 determine whether chronic stimulation of intestinal mucosa by interferon-γ (IFN-γ) affects expression and function of the apical membrane Na⁺/H⁺ exchangers NHE2 and NHE3 in rat intestine and Caco-2/bbe (C2) cells. Confluent C2 cells expressing NHE2 and NHE3 were treated with IFN-γ for 2, 24, and 48 h. Adult rats were injected with IFN-γ intraperitoneally for 12 and 48 h. NHE2 and NHE3 activities were measured by unidirectional ²²Na influx across C2 cells and in rat brush-border membrane vesicles. NHE protein and mRNA were assessed by Western and Northern blotting. IFN-γ treatment of C2 monolayers caused a >50% reduction in NHE2 and NHE3 activities and protein expression. In rats, region-specific, time- and dose-dependent reductions of NHE2 and NHE3 activities, protein expression, and mRNA were observed after exposure to IFN-γ. Chronic exposure of intestinal epithelial cells to IFN-γresults in selective downregulation of NHE2 and NHE3 expression and activity, a potential cause of inflammation-associated diarrhea.