Intracerebroventricular (ICV) injections of interleukin-1 beta (IL-1 beta) produced a dose-dependent increase in plasma corticosterone and adrenocorticotropic hormone (ACTH) within 2 hr of injection and then declined over the next 24 hr. Using a potent steroidogenic dose of IL-1 beta (5 ng), ICV injection resulted in suppression of splenic macrophage IL-1 secretion following stimulation by LPS in vitro. Macrophage TGF-beta secretion was not affected, indicating a differential action of ICV IL-1 beta on macrophage cytokine production. Following adrenalectomy (ADX), the suppressive effect of ICV IL-1 beta was reversed and resulted in stimulation of macrophage IL-1 secretion, indicating that the suppression was mediated by adrenocorticol activation. However, surgical interruption of the splenic nerve to eliminate autonomic innervation of the spleen also prevented the macrophage suppressive signal in rats given ICV IL-1 beta. Furthermore, the combination of ADX and splenic nerve section resulted in a potent stimulatory effect of ICV IL-1 beta on splenic macrophage IL-1 secretion which was greater than either ADX or splenic nerve section alone. These results support the concept of a negative feedback on macrophage IL-1 secretion by the central action of IL-1 beta and indicate that both the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system mediate this effect.