INTERLEUKIN-1-BETA PRODUCTION IN THE RABBIT BRAIN DURING ENDOTOXIN-INDUCED FEVER

1. Interleukin-1 beta (IL-1 beta) production in the brain and the spleen was investigated in rabbits made febrile by intravenous (I.v.) injection of endotoxin, or human recombinant IL-1 beta (hIL-1 beta). The endotoxin used in the present study was the lipopolysaccharide (LPS) of Salmonella typhosa endotoxin. 2. Monophasic fever was induced by I.v. injection of a low dose of LPS (0.02 mu g kg(-1)) and biphasic fever by I.v. injection of a large dose of LPS (4 mu g kg(-1)), a sublethal dose of LPS (40 mu g kg(-1)) or hIL-1 beta (2 mu g kg(-1)). 3. In situ hybridization and immunohistochemical studies revealed that, although no IL-1 beta production was observed in the brain at 1 and 3 h after injection of a low dose of LPS (0.02 beta g kg(-1)) or of hIL-1 beta (2 mu g kg(-1)), IL-1 beta production was demonstrated in organum vasculosum laminae terminalis (OVLT) and some cells around the blood vessels in the parenchyma 1 h after 4 mu g kg(-1) LPS. IL-1 beta production was detected throughout the brain after 40 mu g kg(-1) LPS. Pretreatment with indomethacin, an inhibitor of prostaglandin synthesis, did not affect IL-1 beta production in the brain induced by 4 mu g kg(-1) LPS. 4. The cell type which produces IL-1 beta in the OVLT following LPS injection was confirmed to be a macrophage by electron microscopy. The cells producing IL-1 beta in the parenchyma were determined to be microglial cells. 5. Ln the spleen, each dose of LPS induced a significant increase in IL-1 beta production in polymorphonuclear cells and macrophages in the red pulp 1 h after injection. However, 2 mu g kg(-1) hIL-1 beta did not induce IL-1 beta production in the spleen. 6. The present results show clearly that systemic administration of LPS induces IL-1 beta production in the OVLT which may be responsible for induction of the second phase of biphasic fever. The production of IL-1 beta in the OVLT was not attributable to the action of peripherally synthesized IL-1 beta or prostaglandins.