SYSTEMIC BUT NOT CENTRAL ADMINISTRATION OF TUMOR-NECROSIS-FACTOR-ALPHA ATTENUATES LPS-INDUCED FEVER IN RATS

The purpose of this study was to test the hypothesis that tumor necros is factor-alpha (TNF) limits fever induced by lipopolysaccharide (LPS) in rats and to determine whether such antipyretic action of this cyto kine is outside or inside the central nervous system (CNS). The CNS ef fects on LPS-induced fever were tested by injecting a subpyrogenic amo unt (0.20 mu g) of human recombinant TNF (hrTNF) intracerebroventricul arly or by slowly infusing into the anterior hypothalamus an amount pr eviously measured in this brain region during LPS fever (0.24 U in 0.1 3 mu l of artificial cerebrospinal fluid/min). The peripheral effects of this cytokine on LPS fever were tested by injecting 1 mu g/kg of hr TNF intraperitoneally or by intraperitoneal administration of 300 mu g /kg of the hrTNF soluble receptor p80 (hrTNFsr). The core temperature (measured by biotelemetry) during LPS fever was not significantly affe cted by administration of hrTNF intracerebroventricularly or intrahypo thalamically. An intraperitoneal injection of hrTNF (1 mu g/kg) had a significant antipyretic effect on febrile response to LPS (mean temper ature 2-8 h after injections was 37.28 +/- 0.12 degrees C in rats inje cted with hrTNF and LPS vs. 38.73 +/- 0.04 degrees C in rats injected with saline and LPS; analysis of variance among groups, P = 0.0001; Fi sher's protected least significant difference, P < 0.05). When rats we re injected intraperitoneally with hrTNFsr, the febrile response to LP S was enhanced (analysis of variance among groups, P = 0.0001; Fisher' s protected least significant difference, P < 0.05). These results sup port the hypothesis that TNF acts to Limit the magnitude of LPS-induce d fever and that this action occurs outside the CNS.