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L R Leon

Publications and source records attributed to L R Leon.

10 recordsLinked to original sources
PubMed1998

The use of knockout mice to understand the role of cytokines in fever.

1. In most instances, data obtained using knockout mice to dissect the role of cytokines in fever are similar to data obtained by other, more traditional experimental techniques. 2. Interleukin (IL)-1beta appears to be critically involved in fever caused by some routes of infection/inflammation (e.g. localized inflammation with turpentine). This cytokine has only a small role in fevers caused by i.p. injection of lipopolysaccharide (LPS). These IL-1beta-induced fevers in knockout mice appear to be via the induction of IL-6, similar to LPS-induced fevers in rats. Interleukin-6 also appears to be critically involved in turpentine-induced fever. 3. The precise role of tumour necrosis factor (TNF) in fever is controversial. Data obtained from knockout mice lacking both TNF receptors do not support a pyrogenic role for TNF in fever either to i.p. injection of LPS, s.c. injection of turpentine or following caecal ligation and puncture. 4. The roles of these cytokines in fevers induced by injection of LPS, IL-1beta, turpentine and caecal ligation and puncture are summarized. The data show the complexity of the febrile response. Depending on the types of inflammatory/infectious stimuli, different cytokines play important roles. Because other cytokines are thought to be involved in fever (e.g. macrophage inflammatory protein, interferons), considerable work is still needed to dissect the precise roles of cytokines in fever.

Animals↗
PubMed1997

Exacerbated febrile responses to LPS, but not turpentine, in TNF double receptor-knockout mice.

We examined the effects of injections of systemic [lipopolysaccharide (LPS), 2.5 mg/kg or 50 pg/kg ip] or local (turpentine, 100 microl sc) inflammatory stimuli on fever, motor activity, body weight, and food intake in tumor necrosis factor (TNF) double receptor (TNFR)-knockout mice. A high dose of LPS resulted in exacerbated fevers in TNFR-knockout mice compared with wild-type mice for the early phase of fever (3-15 h); the late phase of fever (16-24 h) and fevers to a low dose of LPS were similar in both groups. Motor activity, body weight, and food intake were similarly reduced in both groups of mice after LPS administration. In response to turpentine, TNFR-knockout and wild-type mice developed virtually identical responses to all variables monitored. These results suggest that 1) TNF modulates fevers to LPS dose dependently, 2) TNF does not modulate fevers to a subcutaneous injection of turpentine, and 3) knockout mice may develop cytokine redundancy in the regulation of the acute phase response to intraperitoneally injected LPS or subcutaneously injected turpentine.

Animals↗
PubMed1997

Sickness behavior in mice deficient in interleukin-6 during turpentine abscess and influenza pneumonitis.

Interleukin-6 (IL-6), among other cytokines, is thought to be involved in the regulation of sickness behavior (e.g., anorexia, cachexia, fever, and lethargy) induced by infections bacterial and viral origin) and sterile tissue necrosis (burns and surgical traumas). Mice deficient in IL-6 (IL-6 KO) were generated by gene targeting. Homozygous IL-6 KO male and female mice and their appropriate controls were implanted with biotelemeters to monitor body temperature (Tb) and motor activity (Act). Normal circadian rhythms in Tb and Act as well as rates of food intake and weight gain did not differ significantly between sex-matched IL-6 KO and control groups at 30 degrees C in a 12:12-h light-dark cycle. Sterile tissue damage was induced in mice by subcutaneous injection of turpentine (0.1 ml, left hindlimb). Influenza pneumonitis was induced by intranasal inoculation of mouse-adapted influenza A virus (17.5 plaque-forming units). Lack of IL-6 completely prevented fever, anorexia, and cachexia because of turpentine abscess in both sexes. It did not prevent lethargy, although IL-6 KO mice recovered to normal Act significantly sooner than wild-type mice. Symptoms of sickness were only slightly modified during influenza virus infection in IL-6 KO mice. Attenuation of sickness behavior was more pronounced in IL-6 KO female than in male mice. We conclude that, although IL-6 is induced during both turpentine abscess and influenza infection, this cytokine appears to be more critical in induction of the symptoms of sickness behavior during sterile tissue abscess than during influenza infection.

Abscess↗
PubMed1997

Effect of heat stress on LPS-induced fever and tumor necrosis factor.

Exposure to heat stress leads to both short-term and long-term effects on morbidity. Male rats were exposed to a high ambient temperature of 40 degrees C, which resulted in biotelemetered core body temperature rising to approximately 42 degrees C. This treatment led to a marked enhancement in lipopolysaccharide (LPS)-induced fever at 24 h after exposure to heat stress. The increase in fever was accompanied by a significant suppression in the circulating concentration of tumor necrosis factor. Heat-shock protein-70 measured in liver was elevated by the heat exposure (but not further elevated by the injection of LPS). An enhanced fever to LPS and other inflammatory stimuli found in heat-stressed human subjects could explain the apparent increase in susceptibility to disease.

Animals↗
PubMed1996

The adaptive value of fever.

There is overwhelming evidence in favor of fever being an adaptive host response to infection that has persisted throughout the animal kingdom for hundreds of millions of years. As such, it is probable that the use of antipyretic/anti-inflammatory/analgesic drugs, when they lead to suppression of fever, results in increased morbidity and mortality during most infections; this morbidity and mortality may not be apparent to most health care workers because fever is only one of dozens of host defense responses. Furthermore, most infections are not life-threatening and subtle changes in morbidity are not easily detected.

Adaptation, Physiological↗
PubMed1996

IL-1 type I receptor mediates acute phase response to turpentine, but not lipopolysaccharide, in mice.

This study examined the role of the interleukin-1 (IL-1) type I receptor (IL-1RtI) in the acute phase response (APR) to inflammation in mice. Turpentine (100 microliters/mouse) injected subcutaneously induced fever, lethargy, body weight loss, and anorexia in IL-1RtI wild-type mice. Knockout mice lacking the IL-1RtI were resistant to these effects of turpentine, supporting a role for this receptor in the APR to local inflammation. The intraperitoneal injection of a low (50 micrograms/kg) or high (2.5 mg/kg) dose of lipopolysaccharide (LPS) induced similar APRs in IL-1RtI wild-type and knockout mice. IL-1RtI knockout mice were resistant to the APR induced by peripherally injected murine IL-1 beta, suggesting that it is not the interaction of endogenous IL-1 beta with IL-1RtII that induces an APR to LPS in these mice. We speculate that the absence of IL-1RtI in these knockout mice results in the sensitization of other cytokine pathways to mediate the APR to LPS.

Acute-Phase Reaction↗
PubMedDate not supplied

Cytokines and fever.

Fever is an excellent example of neuroimmunomodulation in that mediators of immunity initiate a pathway to raise the thermoregulatory set-point, resulting in behavioral and physiological responses that increase body temperature. This rise in temperature is thought to be adaptive, facilitating host defenses. Many cytokines are endogenous mediators of fever (i.e. endogenous pyrogens), including interleukin (IL)-, 1 beta, IL-6 and others. Tumor necrosis factor-alpha may be both an endogenous pyrogen and an endogenous antipyretic or cryogen, depending on the nature of the inflammatory stimuli. Although there is evidence that cytokines within the hypothalamus initiate fever, recent findings indicate that the signal to increase these brain cytokines may be neural (i.e. from peripheral nerves), rather than humoral (i.e. circulating endogenous pyrogen).

Animals↗
PubMedDate not supplied

Hemorrhage suppresses fever, interleukin-6, and tumor necrosis factor-alpha responses to lipopolysaccharide in rats.

The purpose of this study was to test the hypothesis that attenuation of the fever response to lipopolysaccharide (LPS) following hemorrhage is accompanied by changes in serum glucocorticoid levels and a decreased bioactivity of TNF-alpha and IL-6 in plasma. Hemorrhage was induced in rats by the withdrawal of 20% of estimated total blood volume. LPS (50 microg/kg) or saline were injected intraperitoneally immediately after the hemorrhage. Blood samples were taken 1.5 h for TNF-alpha bioactivity and corticosterone measurements and 5 h after treatment for IL-6 bioactivity. Body temperature (Tb) was measured by biotelemetry. The 20% hemorrhage led to a significant reduction in hematocrit measured at 1.5 and 5 h after treatment. Furthermore, 20% hemorrhage caused a substantial elevation in serum corticosterone measured by radioimmunoassay at 1.5 h after treatment. This high concentration of corticosterone was not further potentiated by injection of LPS. Hemorrhaged rats treated with LPS responded with a markedly attenuated fever. Both TNF-alpha and IL-6 rises in the circulation due to LPS injection were significantly smaller in hemorrhaged rats compared to nonhemorrhaged LPS-injected rats. However, this degree of hemorrhage did not alter the T(b) or plasma TNF-alpha and IL-6 activity in hemorrhaged rats injected with saline. These results show that the inhibitory effect of hemorrhage on LPS-induced fever may be related to the decreased TNF-alpha and IL-6 activity in plasma. Hemorrhage-induced high level of corticosterone might contribute to the attenuation of fever, perhaps via the suppression of pyrogenic cytokines.

Animals↗