Interleukin-15 (IL-15) is a novel cytokine with actions similar to IL-2 because of common receptor components. Although IL-15 is expressed in colonic epithelial cells and may regulate epithelial cell function, its effects on these cells are not fully defined. We explored the regulatory effects of IL-15 on IL-8 and monocyte-chemoattractant protein-1 (MCP-1) production in the colonic epithelial cell line Caco-2 as well as in freshly isolated human colonic epithelial cells. IL-15 was added to intestinal epithelial cells under various culture conditions. Levels of chemokines were determined by enzyme-linked immunosorbent assay. To determine the elements of the IL-2/IL-15R complex involved we used neutralizing antibodies specific for individual receptor chains. IL-15 down-regulates IL-8 and MCP-1 production in Caco-2 cells as well as in freshly isolated human colonic epithelial cells in a dose-dependent manner. Intestinal epithelial cells became more responsive to IL-15-induced suppression when activated with greater IL-1 doses. Strong chemokine suppression was seen when IL-15 was given prior to, simultaneous with, or after stimulatory agent. Anti-IL-2Rgamma antibodies efficiently blocked (82% inhibition) the suppression induced by IL-15, while anti-IL-2Rbeta antibodies were less effective. The involvement of beta-chain was further suggested by the finding that a mixture of both monoclonal antibodies (mAb) at a suboptimal concentration (1 microgram/ml of each mAb) produced a synergistic inhibitory effect on down-regulation of epithelial chemokine production. These results show that IL-15 can suppress IL-8 and MCP-1 secretion by intestinal epithelial cells. A microenvironment containing high concentrations of IL-15 may alter the recruitment of neutrophils to enterocytes at least partly by inhibiting IL-8 and MCP-1 production.