Intestinal epithelia are in intimate contact with subepithelial and intraepithelial lymphocytes. When stimulated, mucosal lymphocytes generate inflammatory cytokines such as IL-4 and IFN-gamma. We have shown that IFN-gamma directly regulates epithelial function. It is unknown whether IL-4 might influence epithelial function and, if so, whether such influences are similar to or differ from those exerted by IFN-gamma. In this study, we examine the effect of human IL-4 on barrier function, ion transport, and immune accessory ligand expression on T84 cells, a crypt-like epithelial cell line. Basolateral exposure of epithelial monolayers to IL-4 attenuated epithelial barrier function by greater than 65% in a dose (50% of effective dose = 1 U/ml)- and time (t1/2 = 24 h)-dependent fashion, and was inhibitable by neutralizing anti-IL-4 and anti-IL-4R Ab. Stimulated Cl- secretion, as measured by epithelial short circuit current, was diminished by as much as 70% by IL-4. Epithelial preexposure to IL-4 brought about a greater than twofold increase in beta 2 integrin-dependent neutrophil adhesion to epithelial, but retarded neutrophil migration into and across epithelial monolayers. ELISAs revealed that epithelial exposure to IL-4 had no effect on cell surface expression of MHC class I, MHC class II, or ICAM-1. These results indicate that IL-4, like IFN-gamma, may serve to regulate intestinal epithelial function, but that resulting phenotypes may be cytokine specific. We speculate from these data that activation of the basolateral receptor for IL-4 potentially provides a new strategy for damping the cellular component of active inflammation in the intestine.