Intestinal epithelial (Caco-2) cells secrete the chemokine, IL-8, after stimulation with IL-1beta, but not after lipopolysaccharide. Butyrate is a short chain fatty acid derived from the metabolism of intestinal contents by gut bacteria. Butyrate concentrations reflect, therefore, the bacterial microenvironment established within the intestine. We hypothesized that butyrate may alter the secretion of IL-8 by intestinal epithelial cells in response to stimulation by IL-1beta or lipopolysaccharide. Caco-2 cells were incubated in varying concentrations of sodium butyrate (0-20 mM) for 24 h before stimulation with lipopolysaccharide or IL-1beta. IL-8 secretion was measured over 24 h by ELISA. IL-8 mRNA accumulation was detected by Northern blots. Lipopolysaccharide induced the secretion of IL-8 only after Caco-2 cells cells had been cultured with sodium butyrate. Furthermore, butyrate significantly enhanced IL-8 secretion by cells stimulated with IL-1beta. Butyrate also increased IL-8 mRNA accumulation in stimulated Caco-2 cells. Intestinal epithelial cells can, therefore, be primed by butyrate to become activated by lipopolysaccharide and proinflammatory cytokines. This may represent a mechanism by which intestinal epithelial cells can regulate intestinal inflammation in response to changes in the intestinal milieu.