The cytokine interleukin 1 (IL-1) plays an important role in the activation of the hypothalamus-pituitary-adrenal (HPA)-axis and interleukin 6 (IL-6) production during infection or inflammation. Which of the interleukin 1 receptor types mediates these effects is not known. To investigate this issue a pharmacological approach chosen by using recently developed IL-1 receptor type selective ligands. Rats were given one of various doses of recombinant human IL-1β (rhIL-1β; 1 and 10 μg/kg) and of several IL-1β mutants (ΔSND, ΔQGE and ΔI; 1, 10 and 100 μg/kg), that differ in their affinities for the IL-1 type I receptor but have similar affinities for the IL-1 type II receptor. One hour after intravenous administration of rhIL-1β or IL-1β mutants, plasma levels of ACTH, corticosterone (cort) and IL-6 were measured. Doses of 1 and 10 μg/kg rhIL-1β markedly elevated plasma levels of ACTH, cort and IL-6. However, 10-100-fold higher doses of IL-1β mutants ΔSND and ΔQGE and at least 100-fold higher doses of ΔI have to be administered to increase plasma levels of ACTH, cort and IL-6. The potency differences correlate with their respective affinity for the type I receptor but not with that of the IL-1 type II receptor. It is concluded that IL-1β induced ACTH, cort and IL-6 production is mediated by interleukin 1 type I receptors.