We tested the effects of tumor necrosis factor (TNF) soluble receptor (sTNFR) and anti-TNF serum (anti-TNF) administered intraperitoneally on fever induced by lipopolysaccharide (LPS) in mice. Both agents have been shown to block bioactivity of mouse TNF-alpha. Core temperature (Tb) and locomotor activity in unrestrained mice were measured by biotelemetry. Within 1 h from the LPS injection (2.5 mg/kg ip) Tb decreased below normal for 5-6 h and motor activity was depressed for the following 48 h. After this initial reduction, Tb increased and reached a peak at approximately 24 h postinjection. Anti-TNF and sTNFR blocked this "hypothermic phase" after LPS, and the fevers started sooner; however, the levels and time of peak temperature did not change markedly. In addition, a human recombinant TNF-alpha given intraperitoneally abolished fever and prolonged the fall of Tb in mice after LPS. We conclude that the reduction of Tb soon after injection of LPS in mice is dependent on TNF-alpha.

The purpose of this study was to determine, using push-pull perfusion, the levels of interleukin (IL)-1-like, IL-6-like, and tumor necrosis factor-alpha (TNF)-like activity in the anterior hypothalamus during lipopolysaccharide (LPS)-induced fever in rats. Additionally, slow anterior hypothalamic infusions of human recombinant IL-6 (hrIL-6) or TNF (hrTNF) for several hours were performed to determine possible febrile effects of these two cytokines. Artificial cerebrospinal fluid (aCSF) was infused as a control. Samples of cerebrospinal fluid were collected 60 min before and 60, 180, 300, and 420 min after the intraperitoneal injection of LPS. A control group was injected intraperitoneally with saline. The core temperature (measured by biotelemetry) of LPS-injected rats was significantly higher (P < 0.05) than the temperature of the rats injected with saline at 180, 300, and 420 min after the injection. The average postinjection IL-6 levels were significantly higher (P < 0.05) in the LPS-injected group. TNF was significantly higher (P < 0.05) than the baseline only at 180 min. There were no changes in levels of IL-1-like activity. Infusion of hrIL-6 at a level similar to the peak IL-6 level measured during LPS-induced fever resulted in a slowly developing and long-lasting increase in core temperature. Infusion of hrTNF at a level corresponding to the peak TNF level measured during LPS-induced fever did not induce a significant increase in core temperature. These results support the hypothesis that elevated hypothalamic concentrations of IL-6 are involved in the induction of fever elicited by peripheral (intraperitoneal) injection of LPS.

The purpose of this study was to determine, using push-pull perfusion, whether the central pyrogenic action of interleukin-6 (IL-6) during lipopolysaccharide (LPS)-induced fever in rats is induced by interleukin-1 beta (IL-1 beta) and to determine the source of the hypothalamic IL-6 (i.e., from the periphery or from the brain). Samples of cerebrospinal fluid were collected 60 min before and 60, 120, 180, and 240 min after the intraperitoneal injection of LPS or saline as a control. Immediately before the injection of LPS, anti-rat neutralizing IL-1 beta antibody (anti-IL-1 beta) or control immunoglobulin G antibody (IgG) was microinjected into the anterior hypothalamus (AH) of each rat. At the end of the last perfusion, blood was collected by cardiac puncture. Microinjection of anti-IL-1 beta into the AH caused a 58% reduction of LPS fever (measured by biotelemetry). AH microinjection of anti-IL-1 beta or IgG followed by intraperitoneal injection of saline did not result in significant change in core body temperature. AH injection of anti-IL-1 beta also resulted in a 97% reduction in AH IL-6 levels during LPS fever, with the average values of IL-6 for the four post-LPS time points being 113 +/- 50 U/ml for the rats injected with IgG and LPS and 3 +/- 2 U/ml for the rats injected with anti-IL-1 beta and LPS (P = 0.024).(ABSTRACT TRUNCATED AT 250 WORDS)

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The purpose of this study was to test the hypothesis that tumor necrosis factor-alpha (TNF) limits fever induced by lipopolysaccharide (LPS) in rats and to determine whether such antipyretic action of this cytokine is outside or inside the central nervous system (CNS). The CNS effects on LPS-induced fever were tested by injecting a subpyrogenic amount (0.20 microgram) of human recombinant TNF (hrTNF) intracerebroventricularly or by slowly infusing into the anterior hypothalamus an amount previously measured in this brain region during LPS fever (0.24 U in 0.13 microliter of artificial cerebrospinal fluid/min). The peripheral effects of this cytokine on LPS fever were tested by injecting 1 micrograms/kg of hrTNF intraperitoneally or by intraperitoneal administration of 300 micrograms/kg of the hrTNF soluble receptor p80 (hrTNFsr). The core temperature (measured by biotelemetry) during LPS fever was not significantly affected by administration of hrTNF intracerebroventricularly or intrahypothalamically. An intraperitoneal injection of hrTNF (1 microgram/kg) had a significant antipyretic effect on febrile response to LPS (mean temperature 2-8 h after injections was 37.28 +/- 0.12 degrees C in rats injected 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; Fisher's protected least significant difference, P < 0.05). When rats were injected intraperitoneally with hrTNFsr, the febrile response to LPS was enhanced (analysis of variance among groups, P = 0.0001; Fisher's protected least significant difference, P < 0.05). These results support the hypothesis that TNF acts to limit the magnitude of LPS-induced fever and that this action occurs outside the CNS.