Though cholera toxin (CT) and the heat-labile enterotoxin of Escherichia coli (LT) are known to function as mucosal adjuvants, the initiating signals of this phenomenon remain undefined. In this study, human and mouse cell lines were employed to compare the response of intestinal epithelial cells to an array of toxins and toxin mutants with varied activity levels. Activation of the intracellular Akt and ERK pathways are independent of cAMP-inducing abilities of LT-based. Cytokine analyses determined that, in response to active ADP-ribosylating toxins, these epithelial cell lines secrete proteins with various chemokine and cytokine activities, including IL-8 and proinflammatory cytokines such as IL-6. In contrast, levels of these proteins are much reduced when the epithelial cells were treated with inactive mutants or binding subunits alone. Similar patterns were noted in the production of prostaglandins. Furthermore, the mediators studied are elicited not only by the acknowledged intracellular CAMP pathway, but also by activation of the cyclooxygenase pathway within the epithelial cells. We have shown the cyclooxygenase isoform, COX-2, to be responsible for the enterotoxic effect of LT but not the outcome of adjuvanticity. These findings demonstrate the ability of the epithelial cell to respond to ADP-ribosylating toxins in an immune-initating manner and to alter the outcome of this response based on binding or enzymatic activity of the entertoxin
