Intestinal epithelia are in intimate contact with submucosal and intraepithelial lymphocytes. The concentration of intraepithelial lymphocytes increases during inflammatory processes, and, when stimulated, these cells generate cytokines such as interferon-gamma (IFN-gamma). In this study, we examined the effect of recombinant human IFN-gamma on ion transport events in T84 cells, a crypt epithelial cell line widely used to study electrogenic Cl- secretion, the transport event responsible for mucosal hydration. Epithelial exposure to IFN-gamma brought about a marked attenuation in stimulated Cl- secretion, as measured by generation of short-circuit current (ISC). This IFN-gamma-elicited decrease in the Cl- secretory response was present for a variety of specific agonists, appeared largely due to IFN-gamma interactions with the basolateral surface, and did not result from a defect in second messenger generation. Efflux and uptake studies were utilized to functionally define the individual cell surface transport proteins that participate in Cl- secretion and revealed that, in response to epithelial exposure to IFN-gamma, apical Cl- channels and basolateral Na(+)-K(+)-2Cl- cotransporters, K+ channels, and Na-K-adenosinetriphosphatase were all functionally downregulated. [3H]bumetanide binding assays suggested that surface expression of the cotransporter was diminished by > 70% after IFN-gamma preexposure. Concurrently, surface immunofluorescence studies revealed that epithelial exposure to IFN-gamma brought about the induction of major histocompatibility complex (MHC) class II molecule expression on T84 epithelial monolayers and markedly increased MHC class I surface expression. Finally, neutrophil-epithelial adhesion studies revealed that preexposure of epithelial monolayers to IFN-gamma elicited a beta 2-integrin-dependent induction of neutrophil adhesion.(ABSTRACT TRUNCATED AT 250 WORDS)