Interleukin-15 strongly inhibits interleukin-8 and monocyte chemoattractant protein-1 production in human colonic epithelial cells

Interleukin-15 (IL-15) is a novel cytokine with actions similar to IL-2 bec ause 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 th e colonic epithelial cell line Caco-2 as well as in freshly isolated human colonic epithelial cells. IL-15 was added to intestinal epithelial cells un der various culture conditions. Levels of chemokines were determined by enz yme-linked immunosorbent assay. To determine the elements of the IL-2/IL-15 R complex involved we used neutralizing antibodies specific for individual receptor chains. IL-15 down-regulates IL-8 and MCP-1 production in Caco-2 c ells as well as in freshly isolated human colonic epithelial cells in a dos e-dependent manner. Intestinal epithelial cells became more responsive to I L-15-induced suppression when activated with greater IL-1 doses. Strong che mokine suppression was seen when IL-15 was given prior to, simultaneous wit h, or after stimulatory agent. Anti-IL-2R gamma antibodies efficiently bloc ked (82% inhibition) the suppression induced by IL-15, while anti-IL-2R bet a 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 mu g/ml of each mAb) produced a synergis tic inhibitory effect on down-regulation of epithelial chemokine production . These results show that IL-15 can suppress IL-8 and MCP-1 secretion by in testinal epithelial cells. A microenvironment containing high concentration s of IL-15 may alter the recruitment of neutrophils to enterocytes at least partly by inhibiting IL-8 and MCP-1 production.