We have investigated the effects of recombinant human interleukin (IL)-1 alpha, IL-1 beta and IL-6 on the activation of the hypothalamo-pituitary-adrenal axis. We have determined the effects of a single i.p. injection of cytokine on circulating ACTH and corticosterone levels, corticotrophin-releasing factor (CRF) mRNA in the parvocellular cells of the paraventricular nucleus and pro-opiomelanocortin (POMC) mRNA in the anterior pituitary at both 4 h and 24 h after injection. IL-1 alpha had no effect on any of the parameters measured at either time-point. In contrast, IL-1 beta increased CRF mRNA in the parvocellular paraventricular nucleus and POMC mRNA in the anterior pituitary 4 h after injection. Plasma ACTH and corticosterone were increased at 4 h and circulating ACTH was still increased at 24 h after treatment with IL-1 beta. IL-6 had no effect on message levels but did increase circulating ACTH and corticosterone levels both 4 h and 24 h after injection. The mechanism responsible for the increase in circulating ACTH after IL-6 injection is unclear but would appear to be different from that which is activated by IL-1 beta which also results in increased CRF and POMC gene expression.