No abstract

Infection, trauma, and injury result in a stereotypical response that includes loss of food appetite, increased sleepiness, muscle aches, and fever. For thousands of years fever was considered a protective response, and fevers were induced by physicians to combat certain infections. But with the advent of antipyretic drugs, physicians started to reduce fevers, and fever therapy was virtually abandoned. As a result of (1) studies on the evolution of fever, (2) further understanding of just how tightly the process of fever is regulated, and (3) detailed studies on how fever affects host morbidity and mortality, the view of fever as a host defense response has reemerged. However, data indicate that not all fevers are protective and that high fevers are maladaptive. These issues are discussed in the context of the evolution of host defense responses versus modern medical technology. In short, we speculate that patients who would not have survived severe sepsis in the past are now being kept alive and that the occasionally high fevers seen in these patients may be maladaptive.

Previous data support the hypothesis that during inflammation, interleukin (IL)-1 beta and IL-6 are involved in fever, in activation of the hypothalamic-pituitary-adrenal (HPA) axis, and in the induction of eicosanoids. Most of the pathophysiologic effects of IL-1 beta and Il-6 are mediated by prostaglandins (PGs), modulated by other cytokines, and antagonized by glucocorticoids (GC), a final product of the HPA axis. To further test these relationships, we measured changes in body temperature using biotelemetry in mice deficient in genes for IL-1 beta and/or IL-6 (IL-1 beta knockout [KO] and IL-6 KO) following injection with lipopolysaccharide (LPS) to induce systemic inflammation or turpentine to induce local abscess. Circulating IL-6, tumor necrosis factor alpha (TNF-alpha), GC, and PGE2 were measured in these mice after treatment. IL-1 beta KO mice responded with reduced fever and IL-6 KO mice with normal fever to a high dose of LPS. In contrast, neither type of KO mice produced fever to turpentine. PGE2 levels (measured in the circulation) were suppressed in both types of KO mice injected with turpentine. IL-1 beta KO mice showed deficiency in IL-6 following turpentine, but not LPS, injection. LPS-induced increases in TNF-alpha did not differ between IL-1 beta KO mice and their wild-type counterparts, whereas IL-6 KO mice showed exacerbated LPS-induced circulating TNF-alpha. No differences were noted in plasma elevations of GC between KO and wild-type mice following injection of LPS or turpentine, indicating that IL-1 beta and IL-6 are not required for activation of the HPA axis during inflammation. Our data demonstrate that in the mouse, IL-1 beta and IL-6 are critical for the induction of fever during local inflammation, whereas in systemic inflammation they appear only to contribute to fever.

The purpose of this study was to characterize the basic biology of fever to lipopolysaccharide (LPS) in unrestrained mice. Although LPS has been shown to induce fevers in many laboratory animals (e.g., rats, guinea pigs, rabbits), there is some question of whether LPS causes a fall or rise in body temperature (Tb) in mice. Tb was measured by biotelemetry in unrestrained mice maintained at an ambient temperature of 30 degrees C. Intraperitoneal injections of LPS at doses of 1.0, 2.5, and 3.0 mg/kg induced dose-independent prompt decreases of Tb for 5.7 h. After this postinjection reduction, Tb increased and reached a peak at approximately 24 h postinjection. The peak rises in Tb were dose dependent. Changes in Tb due to LPS were accompanied by suppression of locomotor activity. Indomethacin, at a dose that did not affect normal Tb, enhanced the temperature-lowering effect of LPS as well as inhibited the febrile rise of Tb after LPS. Indomethacin did not modify the reduction in activity caused by the injections of LPS. Food intake of the mice was decreased by LPS in a dose-dependent manner, and tolerance developed to a second injection of LPS. We conclude that freely moving mice can develop pronounced and reproducible fevers in response to LPS, which is different in time course, dose-dependent profile, induction of pyrogenic tolerance profile, and mode of inhibition by indomethacin from those responses that have been observed in other species studied so far.

Our observations are the first to document increased metabolism in myocytes through irisin-mediated induction of mitochondrial biogenesis and uncoupling with corresponding gene expression. These observations support the need for further investigation into the therapeutic and pharmacological effects of irisin, as well as development of irisin-based therapy.

This study characterized selected aspects of the acute phase response after intranasal inoculation of mice with two doses of mouse-adapted influenza virus differing in lethality. Mice given 140 plaque-forming units (PFU) of virus (58% survival) gradually decreased food and water intake to nearly zero over 6 days; survivors then slowly increased intakes. Declines in these behaviors were parallel to decreases in body temperature and general locomotor activity and were associated with elevated activities of interleukin-6 (IL-6), tumor necrosis factor-alpha, and interferons in lung lavage fluid. Circulating levels of these cytokines were not increased. After 55,000 PFU of virus (100% mortality), food and water intake fell to near zero within 48 h, temperature and locomotor activity decreased significantly, and activities of IL-1 and IL-6 were elevated in lung lavage fluid. These data show that cytokine activities in the lungs are elevated in a time frame that supports the hypothesis that cytokines could mediate behavioral and physiological changes in mice during acute influenza infections.

This study characterized body temperature (Tb), locomotor activity (Act), and feeding behavior under normal conditions and following injection with lipopolysaccharide (LPS) or inoculation with live influenza virus of transgenic C57/black mice deficient in interleukin-1 beta (IL-1 beta). Tb and Act in freely moving mice were measured by biotelemetry. Mice deficient in IL-1 beta had normal circadian rhythm of Tb but were less active than their control counterparts. Mice injected with LPS (2.5 mg/kg i.p.) responded with a prompt decrease of Tb, which lasted approximately 10 h, followed by a fever in which Tb reached a peak at approximately 24 h postinjection. There was no difference between groups in the early drop of Tb after the LPS; however, the 24-h peak of Tb was lower in IL-1 beta-deficient mice. The anorexic effects of LPS and influenza infection were similar in both groups of mice. In mice given influenza virus (17.5 plaque-forming units, median lethal dose), Tb and Act gradually decreased. The fall of Tb was smaller in the transgenic mice. The mice deficient in IL-1 beta displayed a higher mortality rate due to influenza infection than the control mice. We conclude that deficiency in IL-1 beta results in lower fever following the LPS injection and in impairment of the defense response to infection with influenza.

Gastrointestinal distress, such as diarrhoea, cramping, vomiting, nausea and gastric pain are common among athletes during training and competition. The mechanisms that cause these symptoms are not fully understood. The stress of heat and oxidative damage during exercise causes disruption to intestinal epithelial cell tight junction proteins resulting in increased permeability to luminal endotoxins. The endotoxin moves into the blood stream leading to a systemic immune response. Tight junction integrity is altered by the phosphoylation state of the proteins occludin and claudins, and may be regulated by the type of exercise performed. Prolonged exercise and high-intensity exercise lead to an increase in key phosphorylation enzymes that ultimately cause tight junction dysfunction, but the mechanisms are different. The purpose of this review is to (1) explain the function and physiology of tight junction regulation, (2) discuss the effects of prolonged and high-intensity exercise on tight junction permeability leading to gastrointestinal distress and (3) review agents that may increase or decrease tight junction integrity during exercise.