Erythropoietin augments the cytokine response to acute endotoxin-induced inflammation in humans

Recent studies have shown that erythropoietin (EPO) offers protection against ischemia, hemorrhagic shock and systemic inflammation in many tissues and it has been suggested that EPO has anti-inflammatory effects. With the aim of investigating the potential acute anti-inflammatory effects of EPO in a human in vivo model of acute systemic low-grade inflammation, we measured circulating inflammatory mediators after intravenous administration of Escherichia coli endotoxin (LPS) bolus injection (0.1 ng/kg of body weight) in young healthy male subjects. The subjects were divided into three groups receiving either (1) LPS alone, (2) EPO alone (15,000 IE of rHuEPO) or (3) EPO and LPS. Endotoxin administration alone induced a 3-, 12- and 5-fold increase in plasma concentrations of TNF-α, IL-6 and IL-10, respectively, 3 h after LPS challenge. When EPO was given prior to a bolus injection with endotoxin, the levels of TNF-α and IL-6 were enhanced by 5- and 40-fold, respectively, whereas the endotoxin-induced increase in IL-10 response was not influenced by EPO. In contrast to our hypothesis, we find that EPO augments the acute inflammatory effect.     

NO plays a role in LPS-induced decreases in circulating IGF-I and IGFBP-3 and their gene expression in the liver

In this study, we administered aminoguanidine, a relatively selective inducible nitric oxide synthase (iNOS) inhibitor, to study the role of nitric oxide (NO) in LPS-induced decrease in IGF-I and IGFBP-3. Adult male Wistar rats were injected intraperitoneally with LPS (100 microg/kg), aminoguanidine (100 mg/kg), LPS plus aminoguanidine, or saline. Rats were injected at 1730 and 0830 the next day and killed 4 h after the last injection. LPS administration induced an increase in serum concentrations of nitrite/nitrate (P < 0.01) and a decrease in serum concentrations of growth hormone (GH; P < 0.05) and IGF-I (P < 0.01) as well as in liver IGF-I mRNA levels (P < 0.05). The LPS-induced decrease in serum concentrations of IGF-I and liver IGF-I gene expression seems to be secondary to iNOS activation, since aminoguanidine administration prevented the effect of LPS on circulating IGF-I and its gene expression in the liver. In contrast, LPS-induced decrease in serum GH was not prevented by aminoguanidine administration. LPS injection decreased IGFBP-3 circulating levels (P < 0.05) and its hepatic gene expression (P < 0.01), but endotoxin did not modify the serum IGFBP-3 proteolysis rate. Aminoguanidine administration blocked the inhibitory effect of LPS on both IGFBP-3 serum levels and its hepatic mRNA levels. When aminoguanidine was administered alone, IGFBP-3 serum levels were increased (P < 0.05), whereas its hepatic mRNA levels were decreased. This contrast can be explained by the decrease (P < 0.05) in serum proteolysis of this binding protein caused by aminoguanidine. These data suggest that iNOS plays an important role in LPS-induced decrease in circulating IGF-I and IGFBP-3 by reducing IGF-I and IGFBP-3 gene expression in the liver.     

Effects of lipopolysaccharide on neurokinin A content and release in the hypothalamic-pituitary axis

The administration of bacterial lipopolysaccharide (LPS) markedly affects pituitary secretion, and its effects are probably mediated by cytokines produced by immune cells or by the hypothalamo-pituitary axis itself. Since neurokinin A (NKA) plays a role in inflammatory responses and is involved in the control of prolactin secretion, we examined the in vivo effect of LPS on the concentration of NKA in hypothalamus and pituitary (assessed by RIA) and serum prolactin levels in male rats. One hour after the intraperitoneal administration of LPS (250 microg/rat), NKA content was decreased in the posterior pituitary but not in the hypothalamus or anterior pituitary. Three hours after injection, LPS decreased NKA concentration in the hypothalamus and anterior and posterior pituitary. In all the conditions tested, LPS significantly decreased serum prolactin. We also examined the in vitro effects of LPS (10 microg/ml), interleukin-6 (IL-6, 10 ng/ml) and tumor necrosis factor alpha (TNF-alpha, 50 ng/ml) on hypothalamic NKA release. Interleukin-6 increased NKA release without modifying hypothalamic NKA concentration, whereas neither LPS nor TNF-alpha affected them. Our results suggest that IL-6 may be involved in the increase of hypothalamic NKA release induced by LPS. NKA could participate in neuroendocrine responses to endotoxin challenge.     

TNF-alpha increases sensitivity to LPS in chronically catheterized rats

Patients with severe trauma injury are transiently exposed to increased serum concentrations of tumor necrosis factor-alpha (TNF-alpha). These patients are susceptible to the development of multisystem organ failure (MSOF) triggered by subsequent exposure to bacterial toxins either via infection or increased intestinal permeability. We simulated the cytokine response of trauma by infusing 0.8 or 8.0 microg/kg of TNF-alpha (priming dose) into chronically catheterized rats. After 48 h, rats were challenged with endotoxin [lipopolysaccharide (LPS); 10 or 1,000 microg/kg]. Animals primed with either dose of TNF-alpha and then challenged with 1,000 microg/kg of LPS demonstrated significantly increased mortality, mean peak serum concentrations of interferon-gamma (IFN-gamma), and blood lactate concentrations (P < 0.05) compared with nonprimed animals. Mean peak serum concentrations of IFN-gamma and blood lactate concentrations were increased after challenge with 10 microg/kg of LPS only in animals primed with 8.0 microg/kg of TNF-alpha. Priming with TNF-alpha did not increase mortality after challenge with 10 microg/kg of LPS. These data suggest that both TNF-alpha release and the subsequent exposure to bacterial toxins mediate the pathophysiological progression from trauma to subsequent MSOF.     

Effect of ergotamine on plasma metabolite and insulin-like growth factor-1 concentrations in cows

Bovine plasma was assayed to determine if ergotamine affected plasma metabolite and insulin-like growth factor-1 (IGF-1) concentrations. In Experiment 1, four cows received a single bolus intravenous injection of ergotamine tartrate (19 microg/kg body wt.) or saline vehicle in a crossover design 2 days after prostaglandin-induced luteolysis. Treatmentxtime affected plasma glucose, triglyceride, total cholesterol and IGF-1 concentrations. Glucose and cholesterol were increased after ergotamine. Triglycerides were elevated within 1 h after ergotamine, but were decreased 3 h after ergotamine treatment. Plasma IGF-1 decreased in response to ergotamine. Blood constituents were unchanged after treatment with saline. In Experiment 2, six cows received a single bolus intravenous injection of ergotamine (20 microg/kg body wt.) or saline vehicle in a crossover design 10 days after receiving norgestomet (6 mg) via subcutaneous ear implant. Treatmentxtime affected glucose, triglycerides, total cholesterol and IGF-1 concentrations. Glucose and cholesterol were increased after ergotamine. Triglycerides were elevated 1 h after ergotamine and decreased 3-7 h after ergotamine. Plasma IGF-1 decreased after ergotamine treatment. Blood constituents were unresponsive to the saline vehicle. Results indicated ergotamine altered plasma metabolite and IGF-1 concentrations in cows.     

Anti-shock effect of pituitary adenylate cyclase activating polypeptide (PACAP) on experimental endotoxin shock in dogs

Effects of pituitary adenylate cyclase activating polypeptide with 38 amino acid residues (PACAP-38) on both cardiovascular functions and plasma hormone levels during endotoxin shock were studied in anesthesized dogs. When PACAP-38 (a bolus 420 pmol/kg injection or a bolus 420 pmol/kg injection followed by a continuous 30 pmol/kg/min infusion for 60 min) was administered intravenously 5 min after application of endotoxin, both mean arterial pressure and cardiac output were restored at 10 min. The continuous administration of PACAP-38 was more effective in improving the symptoms of shock. Plasma adrenalin and cortisol levels were significantly increased by both regimens. These results clearly indicate that the anti-shock properties of PACAP-38 may be attributed to its abilities to increase plasma cortisol and adrenalin levels and to stimulate cardiac function.     

Early social isolation alters behavioral and physiological responses to an endotoxin challenge in piglets

Psychosocial stress in the form of maternal deprivation and social isolation during early postnatal life induces persistent alterations in behavioral and physiological mechanisms of adaptation. One consequence may be an increased susceptibility to diseases in later life. Therefore, the aim of the present study was to investigate in domestic piglets the effects of a repeated social isolation (2 h daily from day 3 to day 11 of age) on behavioral, endocrine and immune responses to an endotoxin challenge with lipopolysaccharide (LPS) 1 day or 45 days after the isolation period. Peripheral LPS administration caused serious sickness behavior (somnolence, shivering, vomiting) and provoked profound increases in circulating tumor necrosis factor-alpha (TNF-alpha), ACTH and cortisol concentrations. The prior social isolation treatment enhanced signs of sickness and impaired suckling behavior. Early isolated piglets responded to LPS by an increase of shivering on day 12 and by increased vomiting on day 56 compared to controls. Further, there were considerable delays and reductions of time isolated piglets spent suckling on day 12. The repeated isolation stressor diminished TNF-alpha increases after LPS, whereas stress hormone levels were not significantly affected by isolation treatment. Finally, stronger relationships between signs of sickness and physiological measures were revealed in early isolated piglets. The duration of somnolence in isolated piglets was related to changes of cortisol and TNF-alpha concentrations, and the highest impact on duration of shivering was found for changes in cortisol and corticosteroid binding globulin levels. The present results suggest a sustained adaptive sensitization of coping with infection by social stress experience during early development in piglets.     

Reduced lipopolysaccharide (LPS)-induced nitric oxide production in peritoneal macrophages and inhibited LPS-induced lethal shock in mice by a sugar cane (Saccharum officinarum L.) extract

A sugar cane extract (SCE) has been found to have an immunostimulating effect in several animals. Lipopolysaccharide (LPS) is known to induce endotoxin shock via the production of inflammatory modulators such as tumor necrosis factor (TNF)-alpha and nitric oxide (NO). We examined in the present study the effects of SCE on the TNF-alpha and NO production in LPS-stimulated mice peritoneal cells and the endotoxin shock in mice. The supplementation of SCE to peritoneal macrophages cultured with LPS resulted in a significant decrease in NO production. All the mice injected intraperitoneally with LPS and D-galactosamine (LPS+GalN) died within 24 h. However, a peritoneal injection, but no intravenous or oral administration, of SCE (500-1,000 mg/kg) at 3 to 48 h before the LPS+GalN-challenge resulted in a significantly improved survival rate. These results suggest that SCE had a protective effect on LPS-induced endotoxin shock via one of possible mechanisms involving the suppression of NO production in the mouse peritoneal cavity.     

Enhancement of the acute phase response to a lipopolysaccharide challenge in steers supplemented with chromium

The study examined the effect of chromium supplementation on the response of steers to an LPS challenge. Steers received a premix that added 0 (control; n?=?10) or 0.2 mg/kg of chromium (n?=?10) to the total diet on a dry matter basis for 56 d. Steers were fitted with jugular catheters and rectal temperature (RT) recording devices on d 52. Blood samples were collected and sickness behavior scores assigned to each steer relative to an LPS challenge (0.5 μg/kg) on d 55. Pre-LPS RT were greater in chromium-supplemented than in control steers. Post-LPS RT increased in both treatments, with control steers producing a greater change in RT than chromium-supplemented steers. Sickness behavior scores were greater in control than in chromium-supplemented steers post-LPS (P?=?0.03). Cortisol concentrations did not differ between treatments pre-LPS. Post-LPS cortisol concentrations increased but did not differ due to treatment. Concentrations of IL-4 increased post-LPS but were not affected by treatment pre- or post-LPS. Treatment did not affect pre-LPS TNF-α or IFN-γ. Post-LPS TNF-α and IFN-γ increased in both treatments, with chromium-supplemented steers producing greater TNF-α (P?=?0.005) and IFN-γ (P?=?0.004) than control steers. Pre-LPS IL-6 was greater (P?=?0.027) in chromium-supplemented steers than in control steers. Post-LPS IL-6 increased in both treatments and was greater (P?相似文献   

Effects of vagotomy on serum endotoxin, cytokines, and corticosterone after intraperitoneal lipopolysaccharide

The vagus nerve appears to play a role in communicating cytokine signals to the central nervous system, but the exact extent of its involvement in cytokine-to-brain communication remains controversial. Recently, subdiaphragmatic vagotomy was shown to increase bacterial translocation across the gut barrier and thus may cause endotoxin tolerance. The current experiment tested whether or not vagotomized animals have similar systemic responses to endotoxin challenge as do sham-operated animals. Subdiaphragmatically vagotomized and sham-operated animals were injected intraperitoneally with one of three doses (10, 50, 100 microg/kg) of lipopolysaccharide (LPS) or vehicle, and blood samples were taken at 15, 30, 60, 90, and 120 min after the injection. The intraperitoneal injection of LPS increased circulating LPS levels at all time points examined. In addition, all three doses of LPS significantly increased serum interleukin (IL)-1beta, IL-6, and corticosterone in both control and vagotomized rats. In conclusion, vagotomy itself has no marked effect on circulating endotoxin levels or the production of IL-1beta, IL-6, or corticosterone in blood after an intraperitoneal injection of LPS.     

Inhibition of TNF-alpha production contributes to the attenuation of LPS-induced hypophagia by pentoxifylline

Cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) are assumed to mediate anorexia during bacterial infections. To improve our understanding of the role that these two cytokines serve in mediating infection during anorexia, we investigated the ability of pentoxifylline (PTX), a potent inhibitor of TNF-alpha production, to block the anorectic effects of the bacterial products lipopolysaccharide (LPS) and muramyl dipeptide (MDP) in rats. Intraperitoneally injected PTX (100 mg/kg body wt) completely eliminated the anorectic effect of intraperitoneally injected LPS (100 microg/kg body wt) and attenuated the anorectic effect of a higher dose of intraperitoneally injected LPS (250 microg/kg body wt). Concurrently, PTX pretreatment suppressed low-dose LPS-induced TNF-alpha production by more than 95% and IL-1beta production 39%, as measured by ELISA. Similarly, high-dose LPS-induced TNF-alpha production was reduced by approximately 90%. PTX administration also attenuated the tolerance that is normally observed with a second injection of LPS. In addition, PTX pretreatment attenuated the hypophagic effect of intraperitoneally injected MDP (2 mg/kg body wt) but had no effect on the anorectic response to intraperitoneally injected recombinant human TNF-alpha (150 ug/kg body wt). The results suggest that suppression of TNF-alpha production is sufficient to attenuate LPS- and MDP-induced anorexia. This is consistent with the hypothesis that TNF-alpha plays a major role in the anorexia associated with bacterial infection.     

Evidence for IFN-gamma as a mediator of the lethality of endotoxin and tumor necrosis factor-alpha.

Current evidence indicates that endogenously produced peptide cytokines, most notably TNF-alpha and IL-1, mediate the lethality of experimental endotoxemia. Because circulating serum levels of IFN-gamma can be detected soon after TNF-alpha and IL-1 in response to endotoxin, we investigated the role of IFN-gamma in endotoxin and TNF-alpha lethality. Specific neutralizing antibodies to murine TNF-alpha (anti-TNF-alpha Ab) or murine IFN gamma (anti-IFN-gamma Ab) produced in our laboratory protected mice against the lethality of Escherichia coli endotoxin (LPS) administered 6 h later. Serum IFN-gamma levels 2 h after i.v. LPS were lower in mice treated with anti-TNF-alpha Ab compared to mice that received nonimmune IgG (median less than 2.5 vs 3.0 U/ml, P2 less than 0.05). In contrast, serum TNF-alpha levels 1 h after i.v. LPS peaked more than fourfold higher in mice treated with anti-IFN-gamma Ab compared to controls (median greater than 6400 vs 1405 pg/ml, p2 less than 0.05). Doses of TNF-alpha (300 micrograms/kg) and IFN-gamma (50,000 U) which were well tolerated when given individually were synergistically lethal in combination (0% lethality vs 100% lethality, P2 less than 0.001), and were associated with higher serum levels of IL-6 than with either cytokine alone. Anti-IFN-gamma Ab provided complete protection against exogenous human rTNF-alpha at the LD100 dose (1400 micrograms/kg, p2 less than 0.001), and in fact prevented lethality at doses four- to fivefold greater than the LD100 human rTNF-alpha (up to 6000 micrograms/kg). We conclude that IFN-gamma is synergistic with TNF-alpha, is essential for the lethality of LPS and TNF-alpha, and may have modulating effects on the negative control of serum levels of TNF-alpha after LPS in mice.     

Thermoregulatory responses of rats to conventional preparations of lipopolysaccharide are caused by lipopolysaccharide per se-- not by lipoprotein contaminants

LPS preparations cause a variety of body temperature (T(b)) responses: monophasic fever, different phases of polyphasic fever, and hypothermia. Conventional (c) LPS preparations contain highly active lipoprotein contaminants (endotoxin proteins). Whereas LPS signals predominantly via the Toll-like receptor (TLR) 4, endotoxin proteins signal via TLR2. Several TLR2-dependent responses of immunocytes to cLPS in vitro are triggered by endotoxin proteins and not by LPS itself. We tested whether any T(b) response to cLPS from Escherichia coli 055:B5 is triggered by non-TLR4-signaling contaminants. A decontaminated (d) LPS preparation (free of endotoxin proteins) was produced by subjecting cLPS to phenol-water reextraction. The presence of non-TLR4-signaling contaminants in cLPS (and their absence in dLPS) was confirmed by showing that cLPS (but not dLPS) induced IL-1beta expression in the spleen and increased serum levels of TNF-alpha and IL-1beta of C3H/HeJ mice; these mice bear a nonfunctional TLR4. Yet, both cLPS and dLPS caused cytokine responses in C3H/HeOuJ mice; these mice bear a fully functional TLR4. We then studied the T(b) responses to cLPS and dLPS in Wistar rats preimplanted with jugular catheters. At a neutral ambient temperature (30 degrees C), a low (0.1 microg/kg iv) dose of cLPS caused a monophasic fever, whereas a moderate (10 microg/kg iv) dose produced a polyphasic fever. In the cold (20 degrees C), a high (500 microg/kg iv) dose of cLPS caused hypothermia. All T(b) responses to dLPS were identical to those of cLPS. We conclude that all known T(b) responses to LPS preparations are triggered by LPS per se and not by non-TLR4-signaling contaminants of such preparations.     

Different sensitivity of rabbit heart and skeletal muscle to endotoxin-induced impairment of mitochondrial function.

The involvement of mitochondrial dysfunction in septic disturbances of tissues is controversial. The aim of this study was to investigate the effects of endotoxin-induced sepsis on the function of heart and skeletal muscle mitochondria. Rabbits were made septic by subcutaneous injection of endotoxin (lipopolysaccharide, LPS) from Escherichia coli at concentrations of 100 or 150 microg LPS.kg(-1) 24 h prior to the experiments. Mitochondrial respiration was measured in saponin-skinned muscle fibers and compared with photometrically detected activities of respiratory chain enzymes as well as with function of perfused hearts. In heart fibers a dosage of 100 microg LPS.kg(-1) caused a significant decrease of state 3-respiration for the substrates pyruvate (-38%), octanoyl-carnitine (-38%) and succinate (-30%) with correspondingly decreased respiratory control indexes (RCI). In addition, endotoxin caused a decreased temporal stability of the rate of state 3-respiration. At least in part these changes can be attributed to a reduced activity of complex I + III (-50%) of the respiratory chain. State 4-respiration rates were not significantly altered. The lowered state 3-respiration in heart mitochondria seems to contribute to the impairment of heart muscle function as detected by an increase of coronary vascular resistance (CVR) in endotoxin-treated hearts. Functional properties of mitochondria from M. Vastus lasteralis were not affected by 100 microg LPS.kg(-1) but a higher dosage of 150 microg LPS.kg(-1) caused decreased RCI for the substrates pyruvate (-29%) and octanoyl-carnitine (-32%). Also the activity of complex I + III was not significantly affected at lower dose of endotoxin but decreased (-42%) after treatment with 150 microg LPS.kg(-1). Results demonstrate the involvement of impaired mitochondria in the pathophysiology of septic organ failure and a tissue specificity of endotoxaemia.     

Enhancement of the endotoxin recognition pathway by ventilation with a large tidal volume in rabbits

Ventilation with a small tidal volume (V(t)) is associated with better clinical outcomes than with a large V(t), particularly in critical settings, including acute lung injury. To determine whether V(t) influences the lipopolysaccaharide (LPS) recognition pathway, we studied CD14 expression in rabbit lungs and the release of TNF-alpha by cultured alveolar macrophages after 240 min of ventilation with a large (20 ml/kg) vs. a small (5 ml/kg) V(t). We also applied small or large V(t) to lungs instilled with 50 microg/kg of LPS. The alveolar macrophages collected after large V(t) ventilation revealed a 20-fold increase in LPS-induced TNF-alpha release compared with those collected after small V(t) ventilation, whereas TNF-alpha was undetectable without LPS stimulation. In animals ventilated with a large V(t), the expression of CD14 mRNA in whole lung homogenates and the expression of CD14 protein on alveolar macrophages, assessed by immunohistochemistry, were both significantly increased in the absence of LPS stimulation. A large V(t) applied to LPS-instilled lungs increased the pulmonary albumin permeability and TNF-alpha release into the plasma. These results suggest that mechanical stress caused by a large V(t) sensitizes the lungs to endotoxin, a phenomenon that may occur partially via the upregulation of CD14.     

Endotoxin-induced reduction in biliary indocyanine green excretion rate in a chronically catheterized rat model

Using a nonstressed chronically catheterized rat model in which the common bile duct was cannulated, we studied endotoxin-induced alterations in hepatic function by measuring changes in the maximal steady-state biliary excretion rate of the anionic dye indocyanine green (ICG). Biliary excretion of ICG was calculated from direct measurements of biliary ICG concentrations and the bile flow rate during a continuous vascular infusion of ICG. Despite significant elevations in mean peak serum tumor necrosis factor-alpha (TNF-alpha) concentrations (90.9 +/- 16.2 ng/ml), there was no effect on mean rates of bile flow or biliary ICG clearance after administration of 100 microg/kg endotoxin at 6 or 24 h. Significant differences from mean baseline rates of bile flow and biliary ICG excretion did occur after administration of 1,000 microg/kg endotoxin (mean peak TNF-alpha 129.6 +/- 24.4 ng/ml). Furthermore, when rats were treated with up to 16 microg/kg of recombinant TNF-alpha, there was no change in mean rates of bile flow or ICG biliary clearance compared with baseline values. These data suggest that the complex regulation of biliary excretion is not mediated solely by TNF-alpha.     

Endogenous estrogen mediates a higher threshold for endotoxin-induced myocardial protection in females

Myocardial endotoxin tolerance may be induced in both males and females; however, it remains unknown whether there are mechanistic and threshold differences between the sexes. We hypothesized that endogenous estrogen mediates a higher threshold for endotoxin (ETX)-induced protection in females. Adult proestrus and ovariectomized (OVX) female rats were preconditioned (PC) with intraperitoneal injections of 125 (PC+125) or 500 (PC+500) microg/kg Salmonella typhimurium LPS (ETX) or normal saline (PC-). Twenty-four hours later, injury dose ETX (500 microg/kg) was injected. After 6 h, myocardial function was measured via Langendorff. p38 MAPK and JNK activation and TNF-alpha, IL-1, and IL-6 expression were evaluated. ETX injury significantly decreased left ventricular developed pressure in PC- groups vs. controls. PC+500 regimen protected against ETX injury, resulting in normal cardiac function. PC+125 regimen protected OVX but not proestrus females, which had diminished myocardial function. Activated JNK and TNF-alpha increased in PC- but were diminished in PC+500 animals. Importantly, activated JNK and TNF increased in PC+125 proestrus females, whereas PC+125 OVX females displayed decreases in these molecules. There were no differences in p38 MAPK activation or expression of IL-1 or IL-6. These results demonstrate that proestrus females require a higher stimulus (PC+500) to achieve myocardial protection against ETX injury. Removal of endogenous estrogen (OVX) lowered the preconditioning threshold (PC+125), resulting in protection after lesser injury. Additionally, myocardial JNK and TNF expression was decreased in OVX PC+125 females, which correlated with myocardial function differences. Therefore, we conclude that endogenous estrogen mediates a higher threshold for ETX tolerance in female myocardium.     

Attenuated febrile response to lipopolysaccharide in rats with biliary obstruction

Patients with biliary tract obstruction have unexplained, inordinately high rates of perioperative morbidity and mortality, whereas cholestatic animals display abnormal hypothalamic responses to pyrogenic stimuli. We asked if obstructive cholestasis was associated with abnormal fever generation. Male Sprague-Dawley rats (250 g) underwent laparotomy for implantation of thermistors and either bile duct resection (BDR) or sham operation. After recovery, temperatures were recorded by telemetry and conscious, unrestrained rats in each group were injected intraperitoneally with either interleukin-1beta (IL-1beta;1 microg/kg) or Escherichia coli lipopolysaccharide (LPS; 50 microg/kg). Baseline temperatures in both groups were similar. Febrile responses after IL-1beta injection in BDR and sham groups were not significantly different. However, in response to LPS injection, BDR rats showed an initial hypothermia with a subsequently attenuated febrile response. Administration of anti-tumor necrosis factor-alpha (TNF-alpha) antibody 2 h before LPS injection blocked the LPS-induced hypothermia seen in BDR animals. However, serum levels of TNF-alpha were not significantly different between sham and BDR animals after LPS injection at any time point measured (0, 1.5, and 3 h).