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Host defenses against pathogens are energetically expensive, leading ecological immunologists to postulate that they might participate in energetic trade-offs with other maintenance programs. However, the metabolic costs of immunity and the nature of physiologic trade-offs it engages are largely unknown. We report here that activation of immunity causes an energetic trade-off with the homeothermy (the stable maintenance of core temperature), resulting in hypometabolism and hypothermia. This immunity-induced physiologic trade-off was independent of sickness behaviors but required hematopoietic sensing of lipopolysaccharide (LPS) via the toll-like receptor 4 (TLR4). Metabolomics and genome-wide expression profiling revealed that distinct metabolic programs supported entry and recovery from the energy-conserving hypometabolic state. During bacterial infections, hypometabolic states, which could be elicited by competition for energy between maintenance programs or energy restriction, promoted disease tolerance. Together, our findings suggest that energy-conserving hypometabolic states, such as dormancy, might have evolved as a mechanism of tissue tolerance., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Insects such as locusts and grasshoppers can reduce the effectiveness of pathogens and parasites by adopting different defense strategies. We investigated the behavioral thermopreference of Locusta migratoria manilensis (Meyen) (Orthoptera: Acrididae) induced by the fungus Beauveria bassiana, and the impact this behavior had on the fungal mycosis under laboratory conditions. By basking in higher temperature locations, infected nymphs elevated their thoracic temperature to 30-32.6 °C, which is higher than the optimum temperature (25°C) for B. bassiana conidial germination and hyphal development. A minimum thermoregulation period of 3 h/day increased survival of infected locusts by 43.34%. The therapeutic effect decreased when thermoregulation was delayed after initial infection. The fungus grew and overcame the locusts as soon as the thermoregulation was interrupted, indicating that thermoregulation helped the insects to cope with infection but did not completely rid them of the fungus. A significant enhancement in the number of haemocytes was observed in infected thermoregulating locusts, reaching levels that were even higher than those observed in the controls. In contrast, haemocyte concentration was severely reduced in infected insects that did not thermoregulate. In infected non-thermoregulating locusts, the reduction in haemocyte number was accompanied by an increase in fungal blastospore concentration that was obvious in the haemolymph by day four. In contrast, no circulating blastospores were found in the haemolymph of infected thermoregulating locusts three days post-inoculation. We also examined the phagocytic activity of infected insects in vivo by using fluorescein isothiocyanate (FITC)-labelled silica beads. The proportion of beads that was engulfed by haemocytes in infected, thermoregulating insects was similar to that in the controls throughout the experiment, whereas the rate of phagocytosis in infected, non-thermoregulating insects progressively decreased after infection. These findings demonstrated that behavioural thermoregulation can adversely affect B. bassiana mycosis in infected L. migratoria manilensis, thereby limiting the development of lethal entomopathogenic fungi in locusts. This is apparently accomplished through an increase in the levels of haemocytes, leading to greater phagocytic activity under certain environmental conditions., Competing Interests: The authors have declared that no competing interests exist.

The effect of temperature on physiology mediates many of the challenges that ectotherms face under climate change. Ectotherm immunity is thermally sensitive and, as such, environmental change is likely to have complex effects on survival, disease resistance and transmission. The effects of temperature on immunity will be particularly profound in winter because cold and overwintering are important triggers and regulators of ectotherm immune activity. Low temperatures can both suppress and activate immune responses independent of parasites, which suggests that temperature not only affects the rate of immune responses but also provides information that allows overwintering ectotherms to balance investment in immunity and other physiological processes that underlie winter survival. Changing winter temperatures are now shifting ectotherm immunity, as well as the demand for energy conservation and protection against parasites. Whether an ectotherm can survive the winter will thus depend on whether new immune phenotypes will shift to match the conditions of the new environment, or leave ectotherms vulnerable to infection or energy depletion. Here, we synthesise patterns of overwintering immunity in ectotherms and examine how new winter conditions might affect ectotherm immunity. We then explore whether it is possible to predict the effects of changing winter conditions on ectotherm vulnerability to the direct and indirect effects of parasites., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Fever occurs upon binding of prostaglandin E 2 (PGE 2 ) to EP 3 receptors in the median preoptic nucleus of the hypothalamus, but the origin of the pyrogenic PGE 2 has not been clearly determined. Here, using mice of both sexes, we examined the role of local versus generalized PGE 2 production in the brain for the febrile response. In wild-type mice and in mice with genetic deletion of the prostaglandin synthesizing enzyme cyclooxygenase-2 in the brain endothelium, generated with an inducible CreER T2 under the Slco1c1 promoter, PGE 2 levels in the CSF were only weakly related to the magnitude of the febrile response, whereas the PGE 2 synthesizing capacity in the hypothalamus, as reflected in the levels of cyclooxygenase-2 mRNA, showed strong correlation with the immune-induced fever. Histological analysis showed that the deletion of cyclooxygenase-2 in brain endothelial cells occurred preferentially in small- and medium-sized vessels deep in the brain parenchyma, such as in the hypothalamus, whereas larger vessels, and particularly those close to the neocortical surface and in the meninges, were left unaffected, hence leaving PGE 2 synthesis largely intact in major parts of the brain while significantly reducing it in the region critical for the febrile response. Furthermore, injection of a virus vector expressing microsomal prostaglandin E synthase-1 (mPGES-1) into the median preoptic nucleus of fever-refractive mPGES-1 knock-out mice, resulted in a temperature elevation in response to LPS. We conclude that the febrile response is dependent on local release of PGE 2 onto its target neurons and not on the overall PGE 2 production in the brain. SIGNIFICANCE STATEMENT By using mice with selective deletion of prostaglandin synthesis in brain endothelial cells, we demonstrate that local prostaglandin E 2 (PGE 2 ) production in deep brain areas, such as the hypothalamus, which is the site of thermoregulatory neurons, is critical for the febrile response to peripheral inflammation. In contrast, PGE 2 production in other brain areas and the overall PGE 2 level in the brain do not influence the febrile response. Furthermore, partly restoring the PGE 2 synthesizing capacity in the anterior hypothalamus of mice lacking such capacity with a lentiviral vector resulted in a temperature elevation in response to LPS. These data imply that the febrile response is dependent on the local release of PGE 2 onto its target neurons, possibly by a paracrine mechanism., (Copyright © 2017 the authors 0270-6474/17/375035-10$15.00/0.)

Sepsis is a systemic inflammatory response to infection, accounting for the most common cause of death in intensive care units. Here, we report that peripheral administration of the hypothalamic neuropeptide orexin improves the survival of mice with lipopolysaccharide (LPS) induced endotoxin shock, a well-studied septic shock model. The effect is accompanied by a suppression of excessive cytokine production and an increase of catecholamines and corticosterone. We found that peripherally administered orexin penetrates the blood-brain barrier under endotoxin shock, and that central administration of orexin also suppresses the cytokine production and improves the survival, indicating orexin's direct action in the central nervous system (CNS). Orexin helps restore body temperature and potentiates cardiovascular function in LPS-injected mice. Pleiotropic modulation of inflammatory response by orexin through the CNS may constitute a novel therapeutic approach for septic shock., Competing Interests: The authors declare that no competing interests exist.

Cannabinoid receptor agonists, such as Δ(9)-THC, the primary active constituent of Cannabis sativa, have anti-pyrogenic effects in a variety of assays. Recently, attention has turned to the endogenous cannabinoid system and how endocannabinoids, including 2-arachidonoylglycerol (2-AG) and anandamide, regulate multiple homeostatic processes, including thermoregulation. Inhibiting endocannabinoid catabolic enzymes, monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH), elevates levels of 2-AG or anandamide in vivo, respectively. The purpose of this experiment was to test the hypothesis that endocannabinoid catabolic enzymes function to maintain thermal homeostasis in response to hypothermic challenge. In separate experiments, male C57BL/6J mice were administered a MAGL or FAAH inhibitor, and then challenged with the bacterial endotoxin lipopolysaccharide (LPS; 2 mg/kg ip) or a cold (4 °C) ambient environment. Systemic LPS administration caused a significant decrease in core body temperature after 6 h, and this hypothermia persisted for at least 12 h. Similarly, cold environment induced mild hypothermia that resolved within 30 min. JZL184 exacerbated hypothermia induced by either LPS or cold challenge, both of which effects were blocked by rimonabant, but not SR144528, indicating a CB1 cannabinoid receptor mechanism of action. In contrast, the FAAH inhibitor, PF-3845, had no effect on either LPS-induced or cold-induced hypothermia. These data indicate that unlike direct acting cannabinoid receptor agonists, which elicit profound hypothermic responses on their own, neither MAGL nor FAAH inhibitors affect normal body temperature. However, these endocannabinoid catabolic enzymes play distinct roles in thermoregulation following hypothermic challenges.

Fever is a cardinal response to infection that has been conserved in warm-blooded and cold-blooded vertebrates for more than 600 million years of evolution. The fever response is executed by integrated physiological and neuronal circuitry and confers a survival benefit during infection. In this Review, we discuss our current understanding of how the inflammatory cues delivered by the thermal element of fever stimulate innate and adaptive immune responses. We further highlight the unexpected multiplicity of roles of the pyrogenic cytokine interleukin-6 (IL-6), both during fever induction and during the mobilization of lymphocytes to the lymphoid organs that are the staging ground for immune defence. We also discuss the emerging evidence suggesting that the adrenergic signalling pathways associated with thermogenesis shape immune cell function.

As temperatures change, insects alter the amount of melanin in their cuticle to improve thermoregulation. However, melanin is also central to insect immunity, suggesting that thermoregulatory strategy may indirectly impact immune defense by altering the abundance of melanin pathway components (a hypothesis we refer to as thermoregulatory-dependent immune investment). This may be the case in the cricket Allonemobius socius, where warm environments (both seasonal and geographical) produced crickets with lighter cuticles and increased pathogen susceptibility. Unfortunately, the potential for thermoregulatory strategy to influence insect immunity has not been widely explored. Here we address the relationships between temperature, thermoregulatory strategy and immunity in the fruit fly Drosophila melanogaster. To this end, flies from two separate Canadian populations were reared in either a summer- or autumn-like environment. Shortly after adult eclosion, flies were moved to a common environment where their cuticle color and susceptibility to a bacterial pathogen (Pseudomonas aeruginosa) were measured. As with A. socius, individuals from summer-like environments exhibited lighter cuticles and increased pathogen susceptibility, suggesting that the thermoregulatory-immunity relationship is evolutionarily conserved across the hemimetabolous and holometabolous clades. If global temperatures continue to rise as expected, then thermoregulation might play an important role in host infection and mortality rates in systems that provide critical ecosystem services (e.g. pollination), or influence the prevalence of insect-vectored disease (e.g. malaria)., (© 2014. Published by The Company of Biologists Ltd.)

We propose a new heuristic model that incorporates metabolic rate and pace of life to predict a vertebrate species' investment in adaptive immune function. Using reptiles as an example, we hypothesize that animals with low metabolic rates will invest more in innate immunity compared with adaptive immunity. High metabolic rates and body temperatures should logically optimize the efficacy of the adaptive immune system--through rapid replication of T and B cells, prolific production of induced antibodies, and kinetics of antibody--antigen interactions. In current theory, the precise mechanisms of vertebrate immune function oft are inadequately considered as diverse selective pressures on the evolution of pathogens. We propose that the strength of adaptive immune function and pace of life together determine many of the important dynamics of host-pathogen evolution, namely, that hosts with a short lifespan and innate immunity or with a long lifespan and strong adaptive immunity are expected to drive the rapid evolution of their populations of pathogens. Long-lived hosts that rely primarily on innate immune functions are more likely to use defense mechanisms of tolerance (instead of resistance), which are not expected to act as a selection pressure for the rapid evolution of pathogens' virulence., (© The Author 2014. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.)

Thermoregulation in patients, who suffer from multiple sclerosis (MS) is impaired and may result in either increases or decreases in body temperature. Disturbances in body temperature correlate with acute relapses, and for this reason, it is an important issue in everyday life of those who suffer from MS. Although rat experimental autoimmune encephalitis (EAE) appeared useful for the examination of current therapies against MS, it has not been thoroughly investigated in terms of body temperature. The purpose of this study was to examine the effect of EAE induction on thermal and motor behavior in the rats. Subcutaneous injection of encephalitogenic emulsion into both pads of hind feet of the Lewis rats provoked symptoms of EAE. Body temperature (T(b)) and motor activity of rats were measured using biotelemetry system. We report a significant increase in body temperature within 24 h prior to the EAE manifestation (12 h average of T(b) for EAE induced animals was higher by 1.07 ± 0.06 °C during day-time and by 0.5 ± 0.05 °C during night time in comparison to the control rats). On the other hand, the onset of EAE symptoms was associated with gradual decrease of body temperature, and during the first night-time T(b) was lower by 1.03 ± 0.08 °C in comparison to the control rats. The inhibition of the motor activity started from the night time, 2 days before EAE onset. On the basis of our data, we concluded that the pattern of body temperature changes after EAE induction may be considered as useful symptom (prodrom) to predict precisely the time of EAE onset. Furthermore, we suggest that EAE in rats may be a suitable model to study mechanism of body temperature alternations observed in MS patients.

The variable domain of camelid heavy chain antibody (VHH) is highly heat-resistant and is therefore ideal for many applications. Although understanding the process of heat-induced irreversible denaturation is essential to improve the efficacy of VHH, its inactivation mechanism remains unclear. Here, we showed that chemical modifications predominantly governed the irreversible denaturation of VHH at high temperatures. After heat treatment, the activity of VHH was dependent only on the incubation time at 90 °C and was insensitive to the number of heating (90 °C)-cooling (20 °C) cycles, indicating a negligible role for folding/unfolding intermediates on permanent denaturation. The residual activity was independent of concentration; therefore, VHH lost its activity in a unimolecular manner, not by aggregation. A VHH mutant lacking Asn, which is susceptible to chemical modifications, had significantly higher heat resistance than did the wild-type protein, indicating the importance of chemical modifications to VHH denaturation., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Environmental conditions during early development can profoundly influence an individual's phenotype. Development requires simultaneous maturation and orchestration of multiple physiological systems creating the potential for interaction among key systems and requiring substantial resources. We investigated the influence of thermoregulation on immunocompetence in Wood Duck ducklings (Aix sponsa). At both 1 and 2 days post hatch (dph) we evaluated ducklings' abilities to thermoregulate during a thermal challenge at one of four temperatures (36 [thermoneutral controls], 20, 10, or 5°C). At 3 dph, ducklings received a superficial wound, which was monitored until full recovery to quantify wound healing ability, an ecologically relevant, integrative measure of immune function. We demonstrated that duckling body temperature decreased with increasing thermal challenge severity, thermoregulatory ability increased with age, and thermoregulation had temperature-dependent effects on the immune system. Specifically, a more severe thermal challenge (5°C) resulted in decreased immune performance when compared to a mild challenge (20°C). We conclude that early thermoregulatory experiences are influential in shaping immune responses early in development. Furthermore, our results emphasize that future studies of environmental stressors need to consider multiple physiological endpoints since interaction among systems can result in competing physiological demands., (Copyright © 2013 Wiley Periodicals, Inc.)

Animal body temperature (Tbody) varies over daily and annual cycles, affecting multiple aspects of biological performance in both endothermic and ectothermic animals. Yet a comprehensive comparison of thermal performance among animals varying in Tbody (mean and variance) and heat production is lacking. Thus, we examined the thermal sensitivity of immune function (a crucial fitness determinant) in Vertebrata, a group encompassing species of varying thermal biology. Specifically, we investigated temperature-related variation in two innate immune performance metrics, hemagglutination and hemolysis, for 13 species across all seven major vertebrate clades. Agglutination and lysis were temperature dependent and were more strongly related to the thermal biology of species (e.g., mean Tbody) than to the phylogenetic relatedness of species, although these relationships were complex and frequently surprising (e.g., heterotherms did not exhibit broader thermal performance curves than homeotherms). Agglutination and lysis performance were positively correlated within species, except in taxa that produce squalamine, a steroidal antibiotic that does not lyse red blood cells. Interestingly, we found the antithesis of a generalist-specialist trade-off: species with broader temperature ranges of immune performance also had higher peak performance levels. In sum, we have uncovered thermal sensitivity of immune performance in both endotherms and ectotherms, highlighting the role that temperature and life history play in immune function across Vertebrata.

This review describes how fever is generated as a regulated increase in body temperature. It results from an upward shift in the thermoregulatory set point, mediated by pyrogenic cytokines released from monocytes/macrophages in response to infection or trauma. Evidence will be presented that fever is part of an integrated host defense system, and that failure to generate a fever in response to infection is generally associated with a poorer prognosis., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Diapause is most often observed in insects and is a physiologically dormant state different from other types of dormancy, such as hibernation. It allows insects to survive in harsh environments or extend longevity. In general, larval, pupal, or adult non-diapausing insects possess an innate immune system preventing the invasion of microorganisms into their bodies; however, it is unclear whether this system works under the dormant condition of diapause. We here report the occurrence of innate cellular reactions during diapause using pupae of a giant silkmoth, Samia cynthia pryeri. Scanning electron microscopic analysis demonstrated the presence of two major types of cells in the body fluid isolated from the thoracic region of a pupa. Phagocytosis and encapsulation, characteristics of innate cellular reactions, by these cells were observed when latex beads as foreign targets were microinjected into the internal portion of a pupa. Such behavior by these cells was still observed even when pupae were continuously chilled at 4°C. Our results indicate that innate cellular reactions can work in diapausing insects in a dormant state., (Copyright © 2011 Elsevier Inc. All rights reserved.)

There has been recent interest in understanding trade-offs between immune function and other fitness-related traits. At proximate levels, such trade-offs are presumed to result from the differential allocation of limited energy resources. Whether the costs of immunity are sufficient to necessitate such energy reallocation remains unclear. We tested the metabolic and behavioural response of male zebra finches (Taeniopygia guttata) to the combined effects of thermoregulation and generation of an acute phase response (APR). The APR is the first line of defence against pathogens, and is considered energetically costly. We predicted that at cold temperatures zebra finches would exhibit an attenuated APR when compared with individuals at thermoneutrality. We challenged individuals with bacterial lipopolysaccharide (LPS), an immunogenic compound that stimulates an APR. Following LPS injection, we measured changes in food intake, body mass, activity, and resting and total energy expenditure. When challenged with LPS under ad libitum food, individuals at both temperatures decreased food intake and activity, resulting in similar mass loss. In contrast to predicted energetic trade-offs, cold-exposed individuals injected with LPS increased their nocturnal resting energy expenditure more than did individuals held at thermoneutrality, yet paradoxically lost less mass overnight. Although responding to LPS was energetically costly, resulting in a 10% increase in resting expenditure and 16% increase in total expenditure, there were few obvious energetic trade-offs. Our data support recent suggestions that the energetic cost of an immune response may not be the primary mechanism driving trade-offs between immune system function and other fitness-related traits.

Background: Autoimmune autonomic ganglionopathy is characterized by impairment of multiple autonomic domains of which sudomotor function is among the most common. Many patients with this disorder have difficulties with thermoregulation and anhidrosis. Our objective was to characterize the distribution and severity of sudomotor dysfunction in this disorder., Methods: Sudomotor function was analyzed in a cohort of 21 patients with ganglionic alpha3 nicotinic acetylcholine receptor (nAChR) antibody positive autoimmune autonomic ganglionopathy. Standard measurements of sudomotor function were used including the Thermoregulatory Sweat Test and Quantitative Sudomotor Axon Reflex Test., Results: The clinical presentation in all patients was characterized by widespread sudomotor dysfunction. Sudomotor impairment was predominantly postganglionic in 17 of the 21 patients studied. Higher ganglionic alpha3 nAChR antibody levels resulted in progressive postganglionic predominant dysfunction (postganglionic, r = 0.637, p = 0.002; mixed ganglionic, r = 0.709, p < 0.001). The pattern of anhidrosis on Thermoregulatory Sweat Testing was consistent with a ganglionopathy in the majority of patients (14 of 21) and a distal pattern in a minority of patients (8 of 21). These patterns of anhidrosis coupled with increasing postganglionic dysfunction in a proximal to distal pattern (foot > distal leg > proximal leg > forearm) indicate lesions at both the ganglia and distal axon of the postganglionic sudomotor sympathetic neuron., Conclusions: Our data characterize the unique sudomotor dysfunction in autoimmune autonomic ganglionopathy as widespread, predominantly postganglionic, and a result of lesions at both the ganglia and distal axon. This study provides important support to the hypothesis that this disorder represents a ganglionic neuropathy.

Objective: To evaluate the efficacy of immunotherapy in the treatment of patients with seropositive and seronegative putative autoimmune autonomic ganglionopathy (AAG) using validated autonomic function tests and instruments., Background: AAG is an immune-mediated disorder characterized by prominent and selective involvement of autonomic nerve fibers or ganglia. Treatment with i.v. immunoglobulin (IVIg) or plasma exchange (PE) has been reported to be effective in single case reports., Methods: We studied six patients, four with seropositive and two with seronegative putative AAG, who underwent autonomic function tests and completed two validated questionnaires, to assess autonomic symptoms before and after immunomodulatory treatment. Patients were treated with standard doses of IVIg, PE, or immunosuppressants in a specific sequential therapy protocol depending on clinical response., Results: Of the six patients (all women, mean ages 49.3 +/- 10.6 years), four patients were ganglionic (alpha3) AChR autoantibody positive and two were autoantibody negative. All patients showed clinical improvement after treatment. Sudomotor function assessed by quantitative sudomotor axon reflex test and thermoregulatory sweat test improved in four patients after treatment., Conclusions: Immunomodulatory treatment can be effective in both seropositive and seronegative putative autoimmune autonomic ganglionopathy. Plasma exchange or combined therapy with immunosuppressive agents should be considered in patients who do not benefit from i.v. immunoglobulin alone.

To more fully characterize the sickness response in young (3 mo) and older (24 mo) rats, we measured core body temperature (CBT), activity level, and body weight changes for 7 days following a peripheral immune challenge with Escherichia coli. CBT increases were delayed and blunted during the 12h following infection in older rats. Indeed, in aging subjects the initial response was hypothermia, but this was followed by a significant and prolonged elevation in CBT lasting 3 days. Young rats, in contrast, generated a rapid and robust CBT elevation lasting just over a day. Activity level was significantly reduced only on the day of E. coli administration in both young and older rats. Body weight loss was equivalent in both age groups one day after E. coli administration, although there was a trend for older rats to continue losing more weight across the next 6 days than in young rats. This is the first study to examine CBTs in young and older rats for a protracted amount of time, thereby revealing that aging rats do have an exaggerated, albeit delayed, fever which is in keeping with other exaggerated sickness behavioral responses observed in aging rodents.

Although fever and sickness behavior are common responses to infection, it has been proposed that the sickness behaviors associated with infection, in particular lethargy and fatigue, may be more valuable clinical markers of illness and recovery in patients, than is body temperature alone. Measuring abdominal temperature, food intake and wheel running we therefore determined the dose thresholds and sensitivities of these responses to lipopolysaccharide (LPS). Male Sprague-Dawley rats were randomly assigned to receive one of three LPS doses (10, 50, 250 microg/kg), or saline, subcutaneously. Administration of LPS induced a dose-dependent increase in abdominal temperature and decrease in wheel running, food intake and body mass. Regression analysis revealed that decreased running was the most-sensitive of the sickness responses to LPS administration, with a regression slope of -41%/log microg, compared to the slopes for food intake (-30%/log microg, F(1,2)=244, P=0.004) and body mass (-2.2%/log microg, F(1,5)=7491, P<0.0001). To determine the likelihood that exercise training influenced the sickness responses we measured in our dose-response study we performed a second experiment in which we investigated whether fever and anorexia induced by LPS administration would present differently depending on whether rats had been exercising or sedentary. Six weeks of wheel running had no effect on the magnitude of fever and anorexia induced by LPS administration. Avoidance of physical activity therefore appears to be a more-sensitive indicator of a host's reaction to LPS than is anorexia and fever.

It has recently been established that the febrile response to bacterial endotoxin attenuated late in pregnancy is partially restored by central inhibition of nitric oxide synthase (NOS). To determine if this restoration of the febrile response also extends to warm-seeking behavior, we used a thermocline to allow animals to select their preferred ambient temperature. Near-term pregnant (day 19-20) and aged matched non-pregnant rats were given an i.p. injection of lipopolysaccharide (LPS, 50 microg/kg) and an intracerebroventricular (i.c.v.) injection of an inhibitor of NOS, N(G)-monomethyl-L-arginine acetate salt (L-NMMA, 100 microg) or vehicle. Core body temperature and self-selected ambient temperature were measured for 6 h after injection. Inhibition of brain NOS before LPS injection resulted in a significant febrile response with an associated increase in selected ambient temperature in both near-term and non-pregnant animals. As expected, near-term dams that received i.c.v. vehicle + i.p. LPS did not have a febrile response but displayed a small hypothermic reaction with no change in selected ambient temperature. We conclude that blockade of brain NOS restores maternal hyperthermic and warm-seeking responses to LPS in near-term pregnancy.

It is known that peripherally administered IL-1 and TNFalpha induce fever through mechanisms involving prostaglandin (PG)E2. In this report, we compared the signaling cascade induced in the brain by TNFalpha and IL-1. Peripheral administration of TNFalpha-induced enhanced fever in IL-1 Receptor antagonist KO mice, suggesting that IL-1 is involved in the TNFalpha mediated fever. IL-1alpha, but not TNFalpha, induced fever in IL-1alpha/beta/TNFalpha KO mice, although central administration of TNFalpha-induced fever. Only IL-1alpha, but not TNFalpha, induced IL-6 in the IL-1alpha/beta/TNFalpha KO mouse brain, while both cytokines induced cyclooxygenase (Cox)-2. I.c.v. administration of PGE2 induced only transient fever in contrast to the TNFalpha- or IL-1alpha-induced fever that lasted longer. Taken together, either IL-1 or TNFalpha induction in the brain is required for the response induced by TNFalpha but not by IL-1alpha, and that both Cox-2 and IL-6 induction are required for prolonged febrile response against these cytokines.

There is ample evidence for the occurrence of inflammatory processes in most major neurodegenerative disorders, both in acute conditions such as traumatic brain injury and stroke, and in chronic disorders such as Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis and Parkinson's disease. Studies on inflammatory factors such as pro- and antiinflammatory cytokines in experimental models of neurodegenerative disorders suggest that they are not merely bystanders, but may be involved in the neurodegenerative process. In addition, there are findings indicating that inflammatory factors may have beneficial effects on the nervous system, particularly during development of the nervous system. The challenge is to understand when, where and during which circumstances inflammation and inflammatory factors are positive or negative for neuronal survival and functioning. Some of our studies on cytokines, particularly the interleukin-1 system, are summarised and discussed in relation to neurodegeneration, cognition, and temperature changes.

The role of type I interferons (IFNs) in mediation of acute viral symptoms (fever, somnolence, anorexia, etc.) is unknown. To determine the role of type I IFN in selected symptom development, body temperature and sleep responses to a marginally lethal dose of X-31 influenza virus were examined in mice with a targeted mutation of the IFN receptor type I (IFN-RI knockouts) and compared to wild-type 129 SvEv control mice. Mice were monitored for 48 h to determine baseline temperature and sleep profiles prior to infection, and then for 9 days following infection. Hypothermic responses to virus were perceptible beginning at 64 h post-infection (PI) and were more marked in KO mice until 108 h, when hypothermia became more exaggerated in wild-type controls. Temperatures of wild-type mice continued to decline through day 9 while temperatures in IFN-RI KO mice stabilized. Time spent in non-rapid eye movement sleep (NREMS) increased in KO mice when hypothermia was marked and then returned to baseline levels, while NREMS continued to increase in wild-type mice through day 9. Other sleep parameters [time spent in rapid eye movement sleep (REMS), relative NREMS EEG slow wave activity, NREMS EEG power density] were all reduced in wild-type mice compared to KOs from days 3 to 8 while REMS low frequency EEG power density increased in wild-type relative to KOs. In conclusion, our results indicate that the presence of functional type I IFN slightly ameliorates disease symptoms early in the X-31 infection while exacerbating disease symptoms later in the infection.

A rise in core temperature during fever usually results from change in the thermocontroller characteristics, resulting in an elevation of the set point of body temperature. Time course and extent of natural fevers are variable, but an upper limit (41 degrees C in humans), at which core temperature is maintained for some time and reduced when the set point of body temperature returns to its normal level, rarely is exceeded. Although any rise in body temperature may result from fever, those rises that are not accompanied by supportive changes in thermoeffector activities are termed hyperthermia.

Pregnancy alters the cytokine, prostanoid and core temperature responses of rats to infectious stimuli at a time when blood levels of the endogenous glucocorticoid corticosterone are elevated. Given that glucocorticoids attenuate bacterial pyrogen-induced fever in rats, the present experiments were carried out to test the hypothesis that administration of RU38486, a glucocorticoid type II receptor antagonist, would restore the febrile response to E. coli lipopolysaccharide (LPS) in pregnant rats on day 21 of gestation. Pregnant rats were randomly allocated to one of four experimental groups depending upon whether they received RU38486 (20 mg kg(-1) intragastric) or vehicle followed by E. coli LPS (160 microg kg(-1)i.p.; a minimal dose that elicits maximal febrile response in non-pregnant rats) or vehicle. Basal core temperature was not altered by intragastric administration of RU38486 or vehicle. Following intragastric administration of vehicle, intraperitoneal administration of E. coli LPS produced a significant hypothermia with latency, duration and magnitude of 0.5 h, 2 h and -1.3 degrees C, respectively. Following intragastric administration of RU38486, however, intraperitoneal administration of E. coli LPS elicited only a minimal decrease in core temperature which was not significantly different from control values. Thus, our data provide evidence that endogenous glucocorticoids play a role in modulating the early core temperature response to a relatively large dose of bacterial pyrogen in rats at term of pregnancy.

Reduced splanchnic blood flow and hyperthermia during exercise-heat stress can produce gastrointestinal barrier dysfunction and increased gastrointestinal permeability. This may allow endotoxin to enter the internal environment, causing local and systemic immune responses. These responses may be involved in the cause and outcome of exertional heatstroke. Countermeasures may reduce gastrointestinal permeability and possibly exertional heatstroke occurrence and outcome.

Objective: To report a reduced febrile response to bacterial infections in anorexia nervosa (AN) patients., Method: Four cases were obtained from a retrospective review of charts from the St. Paul's Hospital Eating Disorders Program (Vancouver, Canada). The patients had died or had been admitted to the hospital for treatment of a bacterial infection. In addition, one case was obtained from the Royal Prince Alfred Hospital (Sydney, Australia)., Results: All patients suffered a bacterial infection during the course of AN. None of the patients had a temperature higher than 37 degrees C during the infectious illness., Discussion: The absence of fever in AN may delay the diagnosis of bacterial infection and may be a marker of an impaired immune response. Therefore, alternative methods of investigation are necessary in patients with AN suspected of having a bacterial infection., (Copyright 2003 by Wiley Periodicals, Inc.)

A 6-wk trial was performed with thirty-six lactating Comisana ewes during the summer of 2001. The animals were divided into three groups of 12, which were designated low (LVR), moderate (MVR), and programmed (PROGR) ventilation regimens. In LVR and MVR rooms, fans provided 10 ventilation cycles of 12.5 and 25 min/h, respectively, whereas in the PROGR room, the fan was programmed to operate at 30 degrees C air temperature and 70% relative humidity. Mean ventilation rates were 33, 66, and 173 m3/h per ewe in LVR, MVR, and PROGR rooms. Air concentrations of microorganisms and dust and of gaseous pollutants were measured twice weekly. Respiration rate and rectal temperature were monitored throughout the trial at 1430. Behavioral traits of ewes were recorded once per week from 0930 to 1230. Cell-mediated immune response to phytohemagglutinin at d 3, 20, and 40 and humoral response to chicken egg albumin at d 11, 21, 30, and 40 were determined. At d 37, ewes were injected with 2 IU porcine ACTH/kg body weight(0.75) and subjected to blood sampling for evaluation of cortisol concentrations immediately before and 1, 2, and 4 h after ACTH injection. Milk yield was recorded daily. Individual milk samples were analyzed weekly for composition and renneting parameters and fortnightly for bacteriological characteristics. Averages of temperature-humidity index values were 78.9, 76.8, and 74.5 in LVR, MVR, and PROGR rooms, respectively. The LVR and MVR treatments resulted in higher NH3 and CO2 air concentrations than PROGR treatment (P < 0.05). The LVR and MVR ewes had higher rectal temperatures than PROGR ewes (P = 0.001). LVR animals also exhibited higher idling compared to PROGR (P < 0.01) and lower feeding times than MVR (P < 0.05) and PROGR animals (P < 0.01). Ewes under the LVR treatment displayed significant lower averages of antibody titers and higher plasma cortisol levels than PROGR (P < 0.01) and MVR ewes (P < 0.05) 60 min after ACTH injection. The LVR treatment resulted in lower yields of milk (P < 0.01) and reduced feed efficiency (P < 0.01) than PROGR treatment. Results suggest that a fan-ventilated system, providing ventilation cycles during the warmest hours of the day and the night at a mean ventilation rate of 66 m3/ewe per hour, may sustain the performance and welfare in lactating ewes raised in warm climates during summer. A ventilation regimen, programmed to operate over upper critical air temperature and relative humidity, may be economically unattractive under these conditions.

Background: Infectious, autoimmune, and neurodegenerative diseases are associated with profound psychological disturbances. Studies in animals clearly demonstrate that cytokines mediate illness-associated behavioral changes. However, the mechanisms underlying the respective psychological alterations in humans have not been established yet. Therefore, we investigated the effects of low-dose endotoxemia, a well-established and safe model of host-defense activation, on emotional, cognitive, immunological, and endocrine parameters., Methods: In a double-blind, crossover study, 20 healthy male volunteers completed psychological questionnaires and neuropsychological tests 1, 3, and 9 hours after intravenous injection of Salmonella abortus equi endotoxin (0.8 ng/kg) or saline in 2 experimental sessions. Blood samples were collected hourly, and rectal temperature and heart rate were monitored continuously., Results: Endotoxin had no effects on physical sickness symptoms, blood pressure, or heart rate. Endotoxin caused a mild increase in rectal temperature (0.5 degrees C), and increased the circulating levels of tumor necrosis factor alpha (TNF-alpha), soluble TNF receptors, interleukin (IL)-6, IL-1 receptor antagonist, and cortisol. After endotoxin administration, the subjects showed a transient significant increase in the levels of anxiety (effect size [ES] = 0.55) and depressed mood (ES = 0.66). Verbal and nonverbal memory functions were significantly decreased (ES = 0.55 to 0.64). Significant positive correlations were found between cytokine secretion and endotoxin-induced anxiety (r = 0.49 to r = 0.60), depressed mood (r = 0.40 to r = 0.75), and decreases in memory performance (r = 0.46 to r = 0.68)., Conclusions: In humans, a mild stimulation of the primary host defense has negative effects on emotional and memory functions, which are probably caused by cytokine release. Hence, cytokines represent a novel target for neuropsychopharmacological research.

Interleukin-1beta (IL-1beta) and other cytokines produce fever by stimulating prostaglandin E(2) (PGE(2)) synthesis in thermoregulatory regions of the preoptic area and anterior hypothalamus (POA/AH). Prostaglandin E(2) is thought to raise body temperature, at least in part, by stimulating beta-endorphin release from pro-opiomelanocortin neurons that innervate the POA/AH. In this study, we investigated whether glycyl-glutamine (beta-endorphin(30-31)), an inhibitory dipeptide synthesized from beta-endorphin post-translationally, inhibits IL-1beta and PGE(2)-induced hyperthermia. Hyperthermic sites were identified by microinjecting PGE(2) (3 fmol/1 microl) into the medial preoptic area (mPOA) of conscious, unrestrained rats. Interleukin-1beta (1 U) injection into the same PGE(2) responsive thermogenic sites in the mPOA elicited a prolonged rise in colonic temperature (T(c)) (+1.02+/-0.06 degrees C) that persisted for at least 2 h. Glycyl-glutamine (3 nmol) co-injection into the mPOA inhibited IL-1beta thermogenesis completely (T(c)=-0.18+/-0.22 degrees C). Glycyl-glutamine had no effect on body temperature when given alone to normothermic rats. Co-injection of individual amino acids, glycine and glutamine (3 nmol each amino acid), failed to influence IL-1beta-induced thermogenesis, which indicates that Gly-Gln hydrolysis does not explain its inhibitory activity. Glycyl-glutamine (3 nmol) also prevented the rise in body temperature produced by PGE(2) (PGE(2)=0.89+/-0.05 degrees C; PGE(2) plus Gly-Gln=-0.16+/-0.14 degrees C), consistent with evidence that PGE(2) mediates IL-1beta-induced fever. These findings demonstrate that Gly-Gln inhibits the thermogenic response to endogenous pyrogens.

Objectives: This study examined the hypothesis that oral contraceptives (OC) influence the production of thermoregulatory cytokines, i.e. interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), soluble glycoprotein 130 (s-gp130) and leptin, and that OC-induced changes in oral temperature (T(oral)) are associated with changes in plasma concentrations of these cytokines. To determine if increases in T(oral) are part of a cytokine-driven inflammatory (acute-phase) response, circulating concentrations of the hepatic acute-phase protein C-reactive protein (CRP) were also measured., Methods: Morning T(oral) were measured and blood samples were collected from 18 women (19- to 22-years-old) on two occasions: Once during active pill usage (quasi-luteal (QL) phase) and once when no active pills were taken (quasi-follicular (QF) phase). Plasma cytokine and CRP concentrations were measured by immunoassay., Results: T(oral) and plasma leptin were higher during QL phase (36.4 +/- 0.1 degrees C, 9.3 +/- 1.0 ng/ml) than QF phase (36.1 +/- 0.1 degrees C, p < 0.01; 7.5 +/- 0.7 ng/ml, p < 0.01). Increases in T(oral) correlated with increases in plasma leptin (R = 0.55, p = 0.02) and with progestin dose (R = 0.47, p = 0.05) individually as well as with leptin and progestin combined in a multiple regression (R = 0.68, p = 0.01). Plasma IL-6 correlated with progestin dose (R = 0.62, p = 0.006). Although there were no phase-related differences in plasma IL-6, sIL-6R, s-gp130, or CRP, the variation in CRP between individuals correlated with the IL-6 agonist/antagonist ratio combined with progestin dose in a multiple regression (R = 0.71, p = 0.01)., Conclusions: These results (a) implicate leptin in basal thermoregulation; (b) indicate that progestins have a significant influence on circulating IL-6 concentrations, and (c) are consistent with the concept that plasma CRP concentrations depend upon combined influences of progestins and bioavailable IL-6., (Copyright 2002 S. Karger AG, Basel)

The multiple effects of vagotomy on the thermoregulatory response to systemic inflammation are reviewed (primarily, for the model of intravenous lipopolysaccharide administration in the rat). The following conclusions are drawn. (1) Vagotomy-associated thermoeffector insufficiency is likely to account for the attenuation of the fever response observed in some--but not all--studies; such an insufficiency is, however, preventable by postoperative care, including the use of a liquid diet. (2) The febrile response to low doses of lipopolysaccharide (monophasic fever) is mediated by the hepatic (but not gastric or celiac) vagal fibers, presumably afferent; the same fibers are likely to be involved in the development of tolerance to low doses of circulating endotoxins. (3) Phase 1 of the polyphasic febrile response to moderate doses of lipopolysaccharide involves capsaicin-sensitive afferents (either nonvagal only or both nonvagal and vagal), does not involve cholecystokinin A-receptors, and may involve peripheral prostaglandins. (4) Febrile phase 2 does not require the integrity of abdominal nerve fibers, either vagal or nonvagal, at least in the rat. (5) Phase 3 of the febrile response to intravenous lipopolysaccharide (and perhaps the response to intraperitoneal lipopolysaccharide) involves capsaicin-insensitive vagal fibers, presumably efferent; the involvement of these fibers in febrigenic mechanisms is strongly modulated by an unknown factor. (6) A hepatoceliac vagal, presumably efferent, mechanism ('an anti-inflammatory pathway') counteracts the development of lipopolysaccharide-induced hypothermia and shock.

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).

The role of the central nervous system in the host response to infection and inflammation and modulation of these responses by the hypothalamic-pituitary-adrenal system are well established. In animals, activation of host defense mechanisms increases non-rapid eye movement (NREM) sleep amount and intensity, which, in turn, are thought to support host defense, or the body's ability to defend itself against challenges to its immune system. In humans, the evidence is conflicting. Therefore, we investigated the effects of three placebo-controlled doses of endotoxin on host response, including nocturnal sleep in healthy volunteers. Administered before nocturnal sleep onset, endotoxin dose dependently increased rectal temperature, heart rate, and the plasma levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptors, interleukin (IL)-1 receptor antagonist, IL-6, and cortisol. The lowest dose reliably increased circulating levels of cytokines and soluble cytokine receptors, but it did not affect rectal temperature, heart rate, or cortisol. This subtle host defense activation increased deep NREM sleep amount, often referred to as slow-wave sleep (stages 3 and 4), and intensity (delta power). Conversely, the highest dose of endotoxin disrupted sleep. Whereas it is well established that the endocrine and thermoregulatory systems are very sensitive to endotoxin, this study shows that human sleep-wake behavior is even more sensitive to activation of host defense mechanisms.

We have cloned the first CD8 alpha gene from an ectothermic source using a degenerate primer for Ig superfamily V domains. Similar to homologues in higher vertebrates, the rainbow trout CD8 alpha gene encodes a 204-aa mature protein composed of two extracellular domains including an Ig superfamily V domain and hinge region. Differing from mammalian CD8 alpha V domains, lower vertebrate (trout and chicken) sequences do not contain the extra cysteine residue (C strand) involved in the abnormal intrachain disulfide bridging within the CD8 alpha V domain of mice and rats. The trout membrane proximal hinge region contains the two essential cysteine residues involved in CD8 dimerization (alpha alpha or alpha beta) and threonine, serine, and proline residues which may be involved in multiple O-linked glycosylation events. Although the transmembrane region is well conserved in all CD8 alpha sequences analyzed to date, the putative trout cytoplasmic region differs and, in fact, lacks the consensus p56lck motif common to other CD8 alpha sequences. We then determined that the trout CD8 alpha genomic structure is similar to that of humans (six exons) but differs from that of mice (five exons). Additionally, Northern blotting and RT-PCR demonstrate that trout CD8 alpha is expressed at high levels within the thymus and at weaker levels in the spleen, kidney, intestine, and peripheral blood leukocytes. Finally, we show that trout CD8 alpha can be expressed on the surface of cells via transfection. Together, our results demonstrate that the basic structure and expression of CD8 alpha has been maintained for more than 400 million years of evolution.

Interleukin (IL)-11 is a member of the gp130 family of cytokines. In contrast to IL-6 (another gp130 cytokine), IL-11 does not induce fever in humans. In the present study, the effect of recombinant human IL-11 (hrIL-11) injected intracerebroventricularly on body temperature of afebrile and febrile rats was studied. Results showed that: (i) hrIL-11 in doses of 5, 50 and 500 ng injected into the cerebral ventricles does not alter body temperature in rats; (ii) febrile response induced by intraperitoneal injection of E. coli endotoxin (50 microg/kg) was initiated more rapidly in rats injected with 500 ng of hrIL-11 in the cerebral ventricles, and (iii) the enhancement of the initial phase of fever induced by hrIL-11 was not accompanied by changes in plasma concentrations of IL-6 and tumor necrosis factor (TNF). These results indicate that hrIL-11 is not pyrogenic when administered into the brain ventricles. The data obtained also demonstrate that central application of hrIL-11 alters body temperature in conditions of pyrogenic stimulation, but that this effect is not due to the alterations in plasma concentrations of IL-6 or TNF. These data suggest that during the development of the systemic inflammatory response, activation of gp130 subunit becomes effective in altering body temperature., (Copyright 2000 S. Karger AG, Basel)

Fever improves survival in acute infections, but the effects of increased core temperature on host defenses are poorly understood. Tumor necrosis factor alpha (TNF-alpha) is an early activator of host defenses and a major endogenous pyrogen. TNF-alpha expression is essential for survival in bacterial infections but, if disregulated, can cause tissue injury. In this study, we show that passively increasing core temperature in mice from the basal (36.5 to 37.5 degrees C) to the febrile (39.5 to 40 degrees C) range modifies systemic TNF-alpha expression in response to bacterial endotoxin (lipopolysaccharide). The early TNF-alpha secretion rate is enhanced, but the duration of maximal TNF-alpha production is shortened. We identified Kupffer cells as the predominant source of the excess TNF-alpha production in the warmer animals. The enhanced early TNF-alpha production observed at the higher temperature in vivo could not be demonstrated in isolated Kupffer cells or in precision-cut liver slices in vitro, indicating the participation of indirect pathways. Therefore, expression of the endogenous pyrogen TNF-alpha is regulated by increments in core temperature during fever, generating an enhanced early, self-limited TNF-alpha pulse.

Psychoimmunology has been credited with using the mind as a way to alter immunity. The problem with this concept is that many of the current psychoimmunology techniques in use are aimed at alleviating stress effects on the immune system rather than at direct augmentation of immunity by the brain. Studies in animals provide a model that permits us to approach the difficulties associated with gaining an understanding of the CNS-immune system connection. A particular advantage of using animals over humans is that psychological and social contributions play a less prominent role for animals than for human subjects, since the animals are all inbred and reared under identical controlled conditions. If the insightful information provided by animal studies is correct, then psychotherapy for the treatment of diseases might be made more effective if some aspect of this knowledge is included in the design of the treatment. We emphasize conditioning as a regimen and an acceptable way to train the brain to remember an output pathway to raise immunity. We propose that a specific drug or perception (mild stress, represented by rotation, total body heating or handling) could substitute and kindle the same output pathway without the need for conditioning. If this view is correct, then instead of using conditioning, it may be possible to use an antigen to activate desired immune cells, and substitute a drug or an external environmental sensory stimulus (perception) to energize the output pathway to these cells. Alternatively, monitoring alterations of body temperature in response to a drug or perception might allow us to follow how effectively the brain is performing in altering immunity. Studies with animals suggest that there are alternative ways to use the mind to raise natural or acquired immunity in man.

Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) have been implicated as key mediators in inflammation, morbidity, and mortality associated with sepsis. We examined the role of IL-6 and TNF-alpha signaling on hypothermia, fever, cachexia, anorexia, and survival during sepsis induced by cecal ligation and puncture (CLP) in male and female gene knockout mice. Male wild-type mice developed an initial hypothermia and subsequent fever during sepsis. Male IL-6 knockout mice did not develop fever; rather, they maintained a profound hypothermia during sepsis. Male TNF p55/p75 receptor (TNFR) knockout mice had attenuated hypothermia, but developed a virtually identical fever as wild-type mice. Cachexia did not differ between male wild-type and IL-6 or TNFR knockout mice, whereas anorexia was prolonged in IL-6 knockout mice. Due to the rapid lethality of sepsis in female mice, survival was the only variable we were able to statistically compare among female genotypes. Female wild-type mice had significantly decreased survival compared with male wild-type mice. Survival was significantly enhanced in male and female TNFR knockout mice compared with their wild-type controls. Lack of IL-6 did not affect male or female lethality. These data support the hypothesis that IL-6 is a key mediator of fever and food intake, whereas TNF is responsible for the initial hypothermia and lethality of sepsis in both sexes of mice. The enhanced lethality of CLP-treated female mice supports a role for sex steroids during sepsis.

Heat shock proteins or stress proteins play a role in adaptative thermotolerance. All cells, procaryotic and eucaryotic, are able to respond to different cellular aggressions by the synthesis of these stress proteins. In normal physiological conditions, they are considered as "molecular chaperones" Their actual role in pathology is still unknown; some of these heat shock proteins may be correlated with the degree of aggressiveness of some tumors.

This review focuses on the response of "stress" hormones to heat, exercise (single or repeated bouts), and combinations of these stimuli, with particular reference to their impact upon immune function. Very hot conditions induce a typical stress response, with secretion of catecholamines and cortisol. The catecholamines induce a demargination of leukocytes, and cortisol subsequently causes cells to migrate to lymphoid tissue. Sustained exercise, even in a thermally comfortable environment, induces a larger hormonal response than moderate thermal stress. With moderate exercise, increases in leukocyte numbers are related mainly to plasma norepinephrine concentrations, but with more intense exercise epinephrine concentrations assume a major importance. As exercise continues, plasma cortisol levels also rise, inducing an influx of neutrophils from bone marrow and an efflux of other leukocyte subsets. A combination of exercise and heat stress augments both hormonal and leukocyte responses. But these changes seem to be reversed if temperatures are clamped by exercising in cold water. If a second bout of exercise is performed with an inter-test interval of 30-45 min, neither hormone concentrations nor immune responses show any great cumulative effect under temperate conditions. However, in a hot environment the second exercise bout induces a larger and more persistent neutrophilia. Training influences these various responses mainly by decreasing the stress imposed when exercising at a given absolute work-rate.

Proinflammatory cytokines [interleukin (IL)-1 and -6 and tumor necrosis factor-alpha] function within a complex network, stimulating the release of one another, as well as other cytokine agonists and antagonists. These interactions have not been as widely studied in vivo. Therefore, the following studies measured cytokines in blood and cerebrospinal fluid (CSF) from juvenile rhesus monkeys after intravenous administration of cytokines. IL-1 alpha and IL-1 beta were equally effective in elevating blood levels of IL-6. In contrast, IL-1 beta was the only cytokine that significantly elevated IL-6 levels in the CSF. Interestingly, both IL-1 and IL-6 increased levels of IL-1 receptor antagonist in the blood and comparably stimulated the release of cortisol. A second study confirmed that the IL-1-induced IL-6 in CSF was brain derived and not a result of diffusion from blood. This research extends studies of the cytokine cascade to the central nervous system (CNS), highlighting the brain response to peripheral activation.

Prenatal ethanol exposure and stress have each been shown to have significant effects on the immune system. This study examined the possible interactive effects of prenatal ethanol exposure and exposure to stress later in life on the immune system. Differential vulnerability to these challenges in female and male offspring was assessed. At 5 to 6 months of age, female and male offspring from prenatal ethanol-exposed (E), pair-red (PF), and ad libitum-fed control (C) conditions were exposed to 0, 1 or 3 days of cold (4 degrees C). At the end of the cold period, the proliferative response of splenic lymphocytes to the mitogens concanavalin A (Con A) and pokeweed mitogen (PWM) was assessed. The data demonstrate a significant interactive effect between prenatal ethanol exposure and cold stress in female offspring. After 1 day of cold stress, E females had significantly increased PWM-induced lymphocyte proliferation compared with PF and C females, and significantly increased Con A-induced lymphocyte proliferation compared with PF females. There were no differences in PWM or Con A-induced lymphocyte proliferation among E, PF, and C females after 0 or 3 days of cold stress, nor among E, PF, and C males on any test day. Regardless of prenatal treatment, females exposed to 1 or 3 days of cold had significantly greater basal plasma corticosterone levels than females not exposed to cold. In contrast, only E males exposed to 1 or 3 days of cold had significantly increased basal plasma corticosterone levels, compared with E males not exposed to cold; PF and C males showed no significant change in basal corticosterone after cold stress. These data demonstrate that, in response to the challenge of cold stress, changes in lymphocyte proliferation to PWM and Con A may occur selectively in E females. Moreover, the interactive effects of prenatal ethanol and cold stress may result in enhanced rather than suppressed immune responsiveness.

Experimentally, systemic inflammation induced by a bolus intravenous injection of lipopolysaccharide (LPS) may be accompanied by three different thermoregulatory responses: monophasic fever (the typical response to low doses of LPS), biphasic fever (medium doses), and hypothermia (high doses). In our recent study [Romanovsky, A. A., V. A. Kulchitsky, C. T. Simons, N. Sugimoto, and M. Székely. Am. J. Physiol. (Regulatory Integrative Comp. Physiol.). In press], monophasic fever did not occur in subdiaphragmatically vagotomized rats. In the present work, we asked whether vagotomy affects the two other types of thermoregulatory response. Adult Wistar rats were vagotomized (or sham operated) and had an intravenous catheter implanted. On day 28 postvagotomy, the thermal responses to the intravenous injection of Escherichia coli LPS (0, 1, 10, 100, or 1,000 micrograms/kg) were tested in either a neutral (30 degrees C) or slightly cool (25 degrees C) environment. Three major results were obtained. 1) In the sham-operated rats, the 1 microgram/kg dose of LPS caused at 30 degrees C a monophasic fever with a maximal colonic temperature (Tc) rise of approximately 0.6 degree C; this response was abated (no Tc changes) in the vagotomized rats. 2) At 30 degrees C, all responses to higher doses of LPS (10-1,000 micrograms/kg) were represented by biphasic fevers (the higher the dose, the less pronounced the first and the more pronounced the second phase was); none of these biphasic fevers was altered in the vagotomized animals. 3) In response to the 1,000 micrograms/kg dose at 25 degrees C, hypothermia occurred: Tc changed by -0.5 +/- 0.1 degree C (nadir); this hypothermia was exaggerated (-1.1 +/- 0.1 degrees C) in the vagotomized rats. It is concluded that vagal afferentation may be important in the mediation of the response to minor amounts of circulating LPS, whereas the response to larger amounts is brought about mostly (if not exclusively) by nonvagal mechanisms. This difference may be explained by the dose-dependent mechanisms of the processing of exogenous pyrogens. Vagotomized animals also appear to be more sensitive to the hypothermizing action of LPS in a cool environment; the mechanisms of this phenomenon remain speculative.

Wasted mice bear the spontaneous autosomal recessive mutation wst/wst; this genotype is associated with weight loss beginning at 21 days of age, neurologic dysfunction, immunodeficiency at mucosal sites, and increased sensitivity to the killing effects of ionizing radiation. The pathology underlying the disease symptoms is unknown. Experiments reported here were designed to examine thermoregulation and liver expression of specific cytokines in wasted mice and in littermate and parental controls. Our experiments found that wasted mice begin to show a drop in body temperature at 21-23 days following birth, continuing until death at the age of 28 days. Concomitant with that, livers from wasted mice expressed increased amounts of mRNAs specific for cytokines IL-6 and IL-1, the acute phase reactant C-reactive protein, c-jun, and apoptosis-associated Rp-8 when compared to littermate and parental control animals. Levels of beta-transforming growth factor, c-fos, proliferating cell nuclear antigen, and ornithine amino transferase transcripts were the same in livers from wasted mice and controls. These results suggest a relationship between an acute phase reactant response in wasted mice and temperature dysregulation.

Murine experiments were undertaken to study the impact of acute and chronic exogenous hyperthermia on the functional activity of natural killers. Single hyperthermia of the animals up to 42 degrees C and thermal shock stages were shown to be followed by suppressed activities of natural killer cells. Daily hyperthermia at 43-44 degrees C for 20 min during 3, 5, and 10 days was characterized by the depressed functional activity of natural killers. Hyperthermia for 20 and 30 days revealed no changes in the activity of natural killer cells. It can be assumed that there is a decrease in antitumor responses of the body in acute hyperthermia and in early chronic hyperthermia.

Recent research has demonstrated that specific parameters of the immune system can be augmented by behavioral conditioning. These physiological alterations have been largely achieved by implementation of the conditioned taste aversion paradigm. Fever and sleep alterations are early occurrences within the acute-phase immune response to infection. The present study attempted to concurrently condition these two simultaneous, yet independent, responses. Lipopolysaccharide (LPS) was used as an unconditioned stimulus. When paired with a novel-tasting saccharin solution, a conditioned febrile response was observed. However, the somnogenic effects of LPS were not simultaneously conditionable. The conditioning of fever, as well as other interleukin-1-mediated responses, offers promise in both clinical and experimental applications.