The observation that administration of interleukin-1 (IL-1) to animals activates the hypothalamo-pituitary-adrenocortical (HPA) axis stimulated great interest in the significance and mechanism of this response, and in whether other cytokines have similar activities. Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha) share HPA-activating activity, although they are less potent and effective than IL-1, whereas IL-2 and interferon alpha(IFN alpha) lack activity. Small increases in body temperature occur in response to IL-1, IL-6 and TNF alpha, but these changes are prevented by inhibitors of cyclooxygenase (COX) and do not appear to be related to the HPA-activation. The rapid HPA-activating effects of IL-1 are impaired by COX inhibitors, but the more prolonged HPA activation associated with intraperitoneal injections is not affected, indicating multiple mechanisms for IL-1-induced HPA activation. The HPA response to IL-6 is not sensitive to COX inhibitors, but that to TNF alpha appears to be. The HPA-activating activity of IL-1 is associated with increases in the apparent release of brain noradrenaline (NA) and serotonin (5-HT), but not dopamine, as well as with increased brain tryptophan. The NA changes, but not these in serotonin metabolism and tryptophan, are prevented by COX inhibitors. IL-6 has effects on serotonin and tryptophan like those of IL-1, but no detected effect on NA. TNF alpha has some effect on NA and tryptophan, but only at relatively high doses. IFN alpha lacks activity on these neurochemicals. Manipulation of noradrenergic, but not serotonergic systems alters the IL-1-induced HPA activation, suggesting the involvement of NA. However, brain NA does not appear to be essential for HPA activation in mice.