Injection of a low concentration (0.3 micrograms/kg iv) of interleukin-1 beta (IL-1 beta) produced monophasic fever, but high concentrations (15 micrograms/kg iv) produced biphasic fever in rats. Treatment with IL-1 beta caused dose-dependent rises in the plasma concentration of adrenocorticotropic hormone (ACTH) 30 min after injection. Moreover, significant increases in plasma levels of ACTH were observed 90 and 180 min after injection of the high dose of IL-1 beta. ACTH response induced by IL-1 beta (15 micrograms/kg iv) was suppressed by pretreatment with injection of indomethacin (Indo), a potent inhibitor of prostaglandin (PG) synthesis, in a dose-dependent manner (1 and 10 mg/kg iv). Also, biphasic fever induced by the high dose of IL-1 beta was completely abolished by pretreatment with the intravenous injection of Indo. Intracerebroventricular (icv) injection of Indo (50 micrograms) did not affect febrile and ACTH responses induced by intravenous IL-1 beta, whereas those responses induced by IL-1 beta (2 ng icv) were significantly suppressed by injection of Indo (50 micrograms icv). Although it is possible that intracerebroventricular Indo does not reach the site of intravenous IL-1 beta action within the brain, these results suggest that in rats febrile and ACTH responses induced by intravenous IL-1 beta are caused by IL-1 beta-acting structures outside the blood-brain barrier. It is likely that these structures subsequently synthesize and release PGE2, which in turn induces ACTH and febrile responses in rats.