A brief exposure of pancreatic islets to the cytokine interleukin-1β(IL-lβ) induces an initial stimulatory phase, which is followed by inhibition of islet function and eventuallyβ-cell damage. In the present study we have investigated the effects of IRAP, a blocker of type I IL-1 receptor and actinomycin D, an inhibitor of DNA transcription, on both the stimulatory and inhibitory effects of IL-βon rat pancreatic isletsin vitro. The two test agents counteracted the initial stimulatory actions of IL-1βon both islet glucose-induced insulin release and glucose oxidation rates. Furthermore, cycloheximide, an inhibitor of protein synthesis, could also prevent the early IL-l/?-induced stimulation of insulin release. When islets were exposed for 1 hr to IL-1βand studied after 12 hr, there was a 75% inhibition of glucose induced insulin release, a 50% decrease in glucose oxidation rates and a 30% decrease in (pro)insulin biosynthesis. These effects were completely counteracted by coincubation with IRAP or actinomycin D, but were not affected by coincubation with pertussis toxin. Islet exposure to IL-Ia also induced a 60-80% inhibition of glucose-induced insulin release after 12 hr. As observed with rIL-1β, IRAP was also able to block the suppressive effects of IL-1 a on islet function. Mouse islets exposed for 2 hr to IL-1βand studied after 12 hr presented a 50% decrease in the glucose-induced insulin release. This effect was completely blocked by coincubation with a rat monoclonal antibody generated against the type I mouse IL-1 receptor.These data suggest that most or all effects of IL-lβon rat pancreatic islets are dependent on binding to surface IL-1 receptors and activation of gene transcription. It remains to be clarified which are the second messengers generated following IL-1βbinding to its receptor and which are the gene(s) transcribed following pancreatic islet exposure to the cytokine.