Central action sites of interleukin-1 beta for inducing fever in rabbits

1. Intravenous (I.V.) human recombinant interleukin-1 beta (IL-1 beta) in high doses caused biphasic fever in rabbits. In lower doses it produced only the first phase of fever. 2. Intracerebroventricular (I.C.V.) or intrapreoptic-anterior hypothalamic (IPOAH) injection of IL-1 beta produced a rather rapid and marked increase in rectal temperature. 3. Subcutaneously administered indomethacin partly reduced the first phase and more substantially the second phase of the biphasic fever induced by high doses of I.V. IL-1 beta. The first phase may thus be prostaglandin independent at least in part. 4. In the fever induced by I.C.V. injection of IL-1 beta, subcutaneous indomethacin reduced the elevation of the rectal temperature considerably and delayed the onset of fever. Administration of indomethacin (I.C.V.) caused marked inhibition of the fever induced by a lower I.C.V. dose of IL-1 beta, but with a high dose the onset of the fever was delayed for about 1 h, without the total rise being affected. 5. It is concluded that the first phase of biphasic fever is caused by IL-1 beta acting via an extravascular component of the organum vasculosum laminae terminalis (OVLT) or the circumventricular organs accessible from only the blood side, to release arachidonate metabolites, presumably prostaglandin E2 (PGE2), and the second phase by IL-1 beta acting via the blood-brain interface accessible both from the blood side and the brain side, to release metabolites other than PGE2.