Is fever really a "side-effect" of biological response modifiers?
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Anti-Inflammatory Agents, Non-Steroidal↗
Biomedical subjects
M J Kluger
Publications and source records attributed to M J Kluger.
Drugs for childhood fever.
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Anti-Inflammatory Agents, Non-Steroidal↗
Behavioral thermoregulation in mice inoculated with influenza virus.
Mice housed at 30 degrees C and inoculated with a mouse-adapted influenza virus show a fall in body temperature (Tb) and a decrease in food intake to almost 0 grams per day. This study tested whether the fall in Tb could be accounted for by the decreased food intake and whether the fall in Tb was due to a decrease of thermoregulatory set point or to an inability to maintain Tb at set point level. The fall in Tb of influenza-infected mice was greater than that of food-deprived mice. When food deprived, mice given access to a thermal gradient increased their preference for warmer areas in the gradient and, as a result, Tb did not fall as much as Tb of starved mice not given access to a thermal gradient. When infected with influenza virus, mice given a thermal gradient decreased Tb less and at a slower rate than mice not given a gradient. However, this fall in Tb of influenza-infected mice was greater than that of food-deprived mice given a thermal gradient. Mice given a thermal gradient increased their preference for the warmer temperatures after inoculation; this returned to preinoculation preference for cooler temperatures during the later days of infection despite a continuous fall in Tb. Influenza-infected mice given a thermal gradient survived significantly fewer days than infected mice not given a thermal gradient. We conclude that the influenza-induced fall of Tb in mice cannot be explained solely by the decrease in food intake, and is partially due to a decrease in thermoregulatory set point.
Animals↗
Fever, tumor necrosis factor, and interleukin-6 in young, mature, and aged Fischer 344 rats.
The purpose of this study was to compare the febrile responses of Fischer 344 rats of different ages [young (3-5 mo), mature (12-15 mo), and aged (24-27 mo; n = 8)] to two psychological stress paradigms, cage switch and exposure to an open field, as well as to injection of lipopolysaccharide (LPS). In addition, the cytokines tumor necrosis factor-alpha (TNF) and interleukin-6 were also measured in the plasma of these rats at 90 min postinjection with LPS. There was no significant difference among groups in febrile responses to switching their cages. Exposure to an open field for 30 min resulted in a smaller rise in temperature in the aged rats (0.62 degree C) than in the young rats (1.26 degrees C). This difference disappeared if rats were exposed to an open field for 60 min. Injection of LPS led to fevers that developed at a slower rate in aged rats than in the mature groups. The peak fevers, however, were not different. The activity of interleukin-6 90 min after injection of LPS was higher in aged rats (297,858 U/ml) than in young (17,462 U/ml) and mature rats (28,819 U/ml). TNF levels were also higher in aged rats (16,380 U/ml) compared with young (574 U/ml) and mature rats (36 U/ml). We conclude that although the magnitude of the febrile response is not different among rats of different ages, the rise in body temperature occurs slower in aged rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Human IL-1 receptor antagonist partially suppresses LPS fever but not plasma levels of IL-6 in Fischer rats.
A human recombinant interleukin-1 receptor antagonist (IL-1ra) recognizes the two known IL-1 receptors and blocks the binding and many biological effects of both IL-1 alpha and IL-1 beta. The effectiveness of IL-1ra in modifying the fever and plasma IL-6 responses elicited by lipopolysaccharide (LPS) in vivo was tested in Fischer 344 rats. Animals that received IL-1ra 0.5 mg/kg intraperitoneally followed 10 min later by 10 micrograms/kg of LPS displayed significantly lower mean fever responses 2-4 h after injection than rats that received vehicle and LPS (0.48 +/- 0.13 vs. 0.95 +/- 0.16 degrees C, P = 0.016). Plasma levels of IL-6 at 4 h after injection were not different in IL-1ra-treated rats compared with controls (407,725 vs. 729,169 U/ml). Based on our previous finding that preadministration of antiserum to IL-1 beta markedly suppressed plasma IL-6 after LPS, and recent evidence that molar excesses of IL-1ra blocked IL-1-induced circulating IL-6 levels, the possibility that IL-1 is responsible for the induction of bioactive IL-6 during inflammation cannot be ruled out. Similarly, the inability of the IL-1ra to completely suppress the febrile responses of rats to LPS in the present study may be dose related. Alternatively, the induction of bioactive IL-6 by IL-1 in the rat may be mediated primarily through some receptor other than the type I (e.g., the type II receptor).
Animals↗
Plasma profiles of IL-6-like and TNF-like activities in brain-dead dogs.
The progression to somatic death after brain death is poorly understood. The role of tumor necrosis factor (TNF) and interleukin-6 (IL-6) in this progression is unknown. TNF-like and IL-6-like plasma activities were assayed in a canine model of brain death in the presence and absence of a lipopolysaccharide (LPS) challenge (0.22 micrograms/kg). Bioassays for TNF-like and IL-6-like activities used WEHI and B9 cell lines, respectively. Brain death was induced by elevating and maintaining intracranial pressure above systolic arterial pressure. Anesthesia and the operative procedure did not cause a significant increase of either cytokine. Brain death (n = 8) itself did not cause a significant elevation of either cytokine compared with the sham brain-death control (n = 6) despite a significant decrease in mean arterial pressure (35 +/- 3 vs. 115 +/- 5 mmHg at 5 h). The brain-dead group treated with LPS (n = 6) responded with a significant elevation in IL-6-like and TNF-like activities compared with the vehicle-treated group. The rise of IL-6-like activity in response to LPS was greater in the brain-dead group than in the sham brain-dead group (n = 3); no significant difference was noted for the TNF-like response. We conclude that the progression to somatic death after brain death cannot be explained by increases in circulating TNF-like or IL-6-like activities.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Role of gram-negative and gram-positive gastrointestinal flora in temperature regulation of mice.
An earlier study showed that the presence of gut flora elevates body temperature of mice and rats. In these experiments, we questioned whether the signal coming from the gut was endotoxin from gram-negative (Gm-) bacteria or some signal derived from gram-positive (Gm+) microorganisms. To test the idea that endotoxin is responsible for the effects of flora, we compared the temperature of the endotoxin-resistant mouse (C3H/HeJ) with that of endotoxin-sensitive strains of mice (C3H/SnJ and C3H/HeN). Temperature of C3H/HeJ was not different from that of C3H/SnJ or C3H/HeN during the light period but was significantly lower during the later hours of the dark period. We speculated that, if endotoxin leaking across the gut wall were responsible for elevating temperature, then reduction of gut flora with nonabsorbable antibiotics would depress the temperature of the endotoxin-sensitive mice more than that of the endotoxin-resistant mice. Because antibiotics lowered the temperature of both strains of mice to the same extent, the signal coming from the gut is unlikely to be endotoxin. To test whether Gm+ flora can be responsible for elevating temperature, we inoculated one group of germfree mice with Gm+ organisms. Their mean temperature was significantly higher than that of mice that remained germfree. Cecectomy had no effect on temperature, indicating that the special properties of the germfree cecum were not involved in lowering the temperature of germfree mice. These data support the hypotheses that Gm+ organisms are a major source of the stimulatory effect of flora on normal body temperature and that the presence of Gm- organisms is unnecessary.
Animals↗
Fever: role of pyrogens and cryogens.
The biology of cytokines is one of the most rapidly growing areas of biomedical research. It is understandable why the assumption was made several years ago that EP was equivalent to IL-1 (both alpha and beta) and subsequently to IL-1 alpha, IL-1 beta, and TNF. However, as more data have been obtained, it has become clearer that many cytokines and hormones are capable of participating in the febrile response. It is also becoming apparent that EPs and ECs might influence body temperature during nonpathological states, perhaps contributing to the elevation in temperature during or after exercise, the circadian variation in temperature, and others. Medical textbooks have begun to list IL-1 as the EP. As I attempted to make clear in this review, evidence that IL-1 alpha is a circulating EP is poor. The evidence is considerably stronger that IL-1 beta is an EP, at least during LPS-induced fever in rodents. The point I have tried to emphasize is that before any cytokine or hormone can be characterized as an EP or EC (or, for that matter, as being involved in any of the acute phase responses), clearly established rules must be followed, which are patterned after the traditional criteria used by Koch to distinguish a pathogenic microorganism from a benign one. As summarized in Tables 4 and 5, there are many candidates for EPs and ECs, but much more experimental evidence is essential before we gain a clear understanding of the relationship between contact with an exogenous pyrogen, the release of EPs and ECs, and the development of fever.
Animals↗
The effects of psychological stress on plasma interleukin-6 activity in rats.
The purpose of this study was to determine the effects of a particular psychological stress, exposure to an open-field, on plasma IL-6 activity in rats. Plasma IL-6 activity was 40.6 +/- 7.2 units/ml in control rats, 105 +/- 6.8 units/ml after 30 minutes exposure to an open-field, and 221 +/- 17 units/ml after 60 minutes of exposure (p = 0.0003). There was a positive correlation (r = .71, p = 0.043) between the change in plasma IL-6 activity and body temperature. However, we conclude, based on earlier data relating plasma IL-6 activity to body temperature changes following injection of lipopolysaccharide, that the plasma levels of IL-6 following exposure to an open-field are not high enough to account for the rise in body temperature observed in rats during this stress. In conclusion, these experiments indicate that exposure to psychological stress can elevate the plasma concentration of IL-6, a known mediator of the acute phase response.
Animals↗
Stress-induced rise of body temperature in rats is the same in warm and cool environments.
Several forms of psychological stress result in a rise in body temperature in rats. In this study, we report that rats housed at a low ambient temperature (11.1 degrees C) develop stress-induced rises in body temperature that do not differ from the responses seen when the animals are kept at a temperature within their thermoneutral zone (24.7 degrees C). These data support the hypothesis that stress-induced "hyperthermia" is a regulated rise in temperature (i.e., a rise in thermoregulatory "set-point," or fever), and is not simply the result of metabolic changes associated with the stress response itself.
Animals↗
Beta-hydroxybutyrate and response to hypoxia in the ground squirrel, Spermophilus tridecimlineatus.
1. Previous studies have suggested that elevated ketone levels are associated with increased survival time in rodents exposed to hypoxia. In this study the association between whole blood BHB (beta-hydroxybutyrate) and hypoxic survival time was investigated in hibernating and non-hibernating ground squirrels and in rats. 2. Non-hibernating ground squirrels and rats were exposed to hypoxia (4.5% O2). One hundred per cent of ground squirrels survived 1 hr of hypoxia vs 20% of rats. 3. Ketone levels were significantly higher in ground squirrels than rats during hypoxia, and rats surviving the longest had the highest ketone levels. 4. When hibernation was induced in ground squirrels there was a significant increase in beta-hydroxy-butyrate from 0.45 to 1.6 mM (P = 0.0005). 5. Ground squirrel heart mitochondrial respiratory control ratios and ATP synthesis rates indicated no preferential ketone utilization which might suggest a possible extramitochondrial role of BHB during hypoxia. 6. We conclude that elevated blood BHB levels are associated with increased hypoxic survival and they may have evolved in response to life-threatening hypoxia as experienced during hibernation.
3-Hydroxybutyric Acid↗
In vivo evidence that the rise in plasma IL 6 following injection of a fever-inducing dose of LPS is mediated by IL 1 beta.
Although it has often been speculated that Interleukin (IL) 1 alpha and IL 1 beta are circulating endogenous pyrogens (EP), there are few data demonstrating an elevation of these cytokines in the plasma of febrile animals. We hypothesized that IL 1 is released locally and may act to stimulate the release of another pyrogen, IL 6, which circulates to the brain to cause fever. The major purpose of the present study was to determine whether pretreatment of rats with antiserum to IL 1 beta, which attenuates lipopolysaccharide (LPS) induced fever, also results in an attenuation of the rise in plasma and cerebrospinal fluid (CSF) concentrations of IL 6. Our results show that injection of IL 1 beta produced dose-dependent rises in temperature and increases in plasma and CSF IL 6 activity, and that pretreatment of rats i.v. with antiserum to IL 1 beta produced a 55% decrease in the fever caused by LPS injection, a 68% decrease in plasma IL 6, and a 67% decrease in CSF IL 6. These data confirm the findings of previous studies that IL 1 beta is required for a portion of LPS-induced fever and also provide the first in vivo demonstration that the rise of IL 6 in rats injected with a fever-inducing dose of LPS can be significantly blocked by antiserum to IL 1 beta. Overall, the data in our study can be interpreted as being consistent with the hypothesis that the pyrogenic effect of IL 1 beta is mediated mainly through the release of IL 6, but conclusive confirmation of this hypothesis must await studies with antibodies to IL 6.
Animals↗
The effects of pentoxifylline on lipopolysaccharide (LPS) fever, plasma interleukin 6 (IL 6), and tumor necrosis factor (TNF) in the rat.
The purpose of these studies was to test whether pentoxifylline, a drug that can inhibit the production and action of cytokines hypothesized to be endogenous pyrogens (for example, interleukin 1 and tumor necrosis factor [TNF]), is antipyretic. We also tested the effects of pentoxifylline on plasma activities of interleukin 6 (IL 6) and TNF in response to an injection of a fever-inducing dose of lipopolysaccharide (LPS). Our results showed that a high dose of pentoxifylline (200 mg/kg) caused hypothermia in control rats and blocked LPS fever, while a low dose (50 mg/kg) did not have these effects. Injection of the high dose of pentoxifylline in control rats caused a rise in plasma IL 6 but not in plasma TNF. However, the peak levels of plasma IL 6 and TNF activities following an injection of LPS were significantly reduced by pretreatment with pentoxifylline. Overall, the data are consistent with the hypothesis that pentoxifylline is an antipyretic drug, which may act at least in part by inhibiting the secretion of pyrogenic cytokines.
Animals↗
Antiserum against tumor necrosis factor enhances lipopolysaccharide fever in rats.
The role of tumor necrosis factor (TNF, cachectin), a putative endogenous pyrogen, was investigated by comparing fever and plasma TNF levels after the intraperitoneal and intramuscular injection of 10 micrograms/kg lipopolysaccharide (LPS) into male Sprague-Dawley rats and by neutralization of endogenous TNF using TNF antiserum. An intraperitoneal injection of LPS caused a biphasic fever that lasted approximately 6.5 h. TNF levels in these rats peaked at 657 +/- 222 U/ml at 1 h then declined to virtually undetectable levels by the fourth hour. The intramuscularly injected animals showed a lower monophasic fever and low sustained TNF levels (40 +/- 10 U/ml at 1 h, 18 +/- 11 U/ml at 4 h). In a second study, an antiserum that had been shown to neutralize rat TNF was injected intraperitoneally 2 h before the intramuscular injection of 10 micrograms/kg LPS. Control rats were injected with normal rabbit serum before LPS. During the second hour after the injection of LPS, the animals that received the antiserum developed fevers that tended to be lower than those seen in the rats that were injected with control serum (0.33 +/- 0.06 vs. 0.58 +/- 0.1), although this difference was not significant. However, during the third through eighth hours after LPS, the antiserum-injected rats had mean body temperatures that were significantly higher than those of the control rats (1.62 +/- 0.11 vs. 1.07 +/- 0.09; P = 0.0005).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effect of gastrointestinal flora on body temperature of rats and mice.
The purpose of these experiments was to test the hypothesis that gut flora influences the body temperature of rodents. Rats and mice were implanted with biotelemetry transmitters that enabled us to record both abdominal temperature and activity for long periods of time. Rats given nonabsorbable antibiotics in their drinking water, which reduced their gut flora, had a marked decrease in both their daytime and nighttime temperatures. Similar results were found with germfree mice. The circadian rhythms in body temperature of germfree and conventionalized mice were not different. However, the body temperatures of the germfree mice were lower than those of the conventionalized mice during both the daytime and nighttime. The decrease in body temperature in the germfree mice was not related to changes in activity. These results support the hypothesis that gut flora has a tonic stimulatory effect on both the daytime and nighttime body temperature of rodents.
Abdomen↗
Antiserum against tumor necrosis factor increases stress hyperthermia in rats.
Psychological stress (e.g., exposure to a novel environment) causes a rapid rise in body temperature in rats. In this study, we examined the roles of physical activity and the immune cytokine tumor necrosis factor or cachectin (TNF) in this temperature change. The elevation in temperature of rats exposed to cage-switch stress during the day correlated poorly with the increase in activity (r = 0.07; P = 0.84) and, during cage switch at night, correlated negatively (r = 0.64; P = 0.04). TNF was not detected in the plasma or cerebrospinal fluid of rats after exposure to open-field stress. However, the injection of antiserum against TNF 3.5 h before exposure to the stress of being in an open field resulted in a significantly greater hyperthermia than was seen in the control serum-injected rats (1.38 +/- 0.11 vs. 0.79 +/- 0.14 degrees C; P = 0.002). The peak temperature change after cage-switch stress was similarly increased in rats that had been injected with anti-TNF (0.82 +/- 0.08 vs. 0.50 +/- 0.08 degrees C; P = 0.016). This enhanced hyperthermia is similar to the excessively high fever that occurs during the later phase of lipopolysaccharide fever in animals that have been injected with antiserum against TNF. These data support the hypotheses that stress hyperthermia is a true fever and that TNF is an endogenous antipyretic, limiting the magnitude of this fever.
Animals↗
Role of interleukin 6 in fever in rats.
The purpose of these studies was to assess whether interleukin 6 (IL-6) is an endogenous pyrogen, responsible for all or part of the fever caused by lipopolysaccharide (LPS) in rats. We have found that the core temperature (as measured by biotelemetry) rose significantly after intracerebroventricular (icv) injection of recombinant human IL-6. The same doses of IL-6, when administered intravenously or intraperitoneally, had no effect on body temperature. The fever caused by icv administration of IL-6 was completely blocked by indomethacin. After injection of fever-inducing doses of LPS, the plasma and cerebrospinal fluid (CSF) IL-6 activities rose, the former much more than the latter. The correlation between fever and plasma IL-6 activity was r = 0.84 (P less than 0.0025); the correlation between fever and CSF IL-6 activity was r = 0.77 (P less than 0.015). The results of this study are consistent with the hypothesis that IL-6 is a mediator of LPS-induced fever in the rat.
Animals↗