[Neurotropic effects of cytokines: at the limits of immunology and neurobiology].
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Brain↗
Biomedical subjects
R Dantzer
Publications and source records attributed to R Dantzer.
[Current studies on the neurobiology of chronic fatigue syndrome].
Cytokines are soluble mediators which are released by activated immune cells during infection and inflammation. The possibility that fatigue is mediated by the effects of cytokines on the central nervous system is supported by several converging lines of evidence: 1) infusions of cytokines to immunocompromised patients induce flu-like symptoms including fatigue and malaise; 2) peripheral and central injection of cytokines to laboratory rodents induce sickness behaviour; 3) symptoms of sickness behaviour occurring during experimental infections can be abrogated by administration of anti-cytokine treatments; 4) although many pitfalls in the detection of cytokines still exist, patients afflicted with the chronic fatigue syndrome have been found in some studies to display instances of excessive production of cytokines. Experimental studies have confirmed that cytokines are interpreted by the brain as internal signals for sickness. Furthermore, there is evidence that sickness is a motivation which reorganizes the organism's priorities in face of this particular threat which is represented by infectious pathogens. The elucidation of the mechanisms that are involved in these effects and in particular, the role of the cytokines which are produced in the brain in response to peripheral immune stimuli and to stressors, should give new insight on the way sickness and recovery processes are organized in the brain.
Adaptation, Psychological↗
Lipopolysaccharide induces sickness behaviour in rats by a vagal mediated mechanism.
To assess the possibility that lipopolysaccharide (LPS) induces sickness behaviour by activating primary afferent nerves, the effects of LPS (1.25 mg kg-1, intraperitoneally) were compared in vagotomized and sham-operated rats. Subdiaphragmatic vagotomy blocked the LPS-induced depression of social investigation but had no effect on LPS-induced increases in levels of IL-1 beta in plasma and peritoneal macrophages and on LPS-induced changes in dehydrogenase activity of peritoneal macrophages.
Animals↗
Animal welfare methodology and criteria.
The concepts of welfare and comfort are relatively new to the veterinary field. For a long time, it was thought that these concepts were equivalent to the absence of pain, stress and suffering, but such a comparison is imprecise. In addition, the application of objective and quantitative criteria to pain and stress has not been as easy as was initially thought. The concept of stress has evolved considerably since the term was coined by H. Selye in the 1950s to denote the non-specific response of an organism to any excessive demand. It is now well established that neurohormonal stress responses do not depend on the physical nature of the stressor, but on the way in which this is perceived and presented to the animal which is exposed to such a situation. The study of stress reactions therefore provides an insight into the subjective world of the animal. Suffering cannot be confined to physical suffering alone, as animals are capable of undergoing mental suffering. Research into the welfare and comfort of animals implies a study of the ability of an animal to express basic species-specific behaviour in the environment in which it is placed. Any discomfort produced by husbandry conditions may be detected through anomalies in the expression of this behaviour, or by examining preferences expressed by animals offered a free choice. All of these elements provide an objective and quantifiable approach to welfare and suffering in animals. But society must determine what is acceptable or not on the basis of these criteria.
Animal Welfare↗
Vasopressin and behavior: from memory to olfaction.
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Animals↗
Role of the vomeronasal system in vasopressinergic modulation of social recognition in rats.
To assess the role of the vomeronasal organ (VNO) in the dependence of social recognition on vasopressinergic transmission, vomerectomized rats were compared to intact and castrated male rats. Removal of the VNO significantly decreased the duration of social investigation and temporarily impaired social recognition. In contrast to sham-operated animals and non-operated animals, lesioned rats were no longer responsive to the blocking effect of the antagonist of the vasopressor receptors of vasopressin (dPTyr(Me)AVP, 30 micrograms/kg subcutaneously) on social recognition. Consequently, VNO-lesioned rats behave like castrates, in spite of the lack of effect of removal of the VNO on plasma testosterone levels. These results suggest that androgen-dependent vasopressinergic neurons are part of the VNO pathway and that the VNO system is important for processing and storage of socially relevant information in male rat.
Animals↗
Central and peripheral prostaglandins are involved in sickness behavior in birds.
Many of the behavioral manifestations of mammals and birds following infection are now recognized as important mechanisms for maintaining homeostasis and promoting recovery. To investigate the role of prostaglandins (PGs) in the behavioral and physiological effects of lipopolysaccharide (LPS) in birds, chickens were injected with indomethacin (Ind) peripherally (IP, 5 mg) or centrally (ICV, 100 micrograms) and their behavior and body temperature following a challenge IP injection of LPS (2.5 mg) were assessed at 1 and 2 h, respectively. Pretreatment with Ind IP or ICV completely inhibited the hyperthermia caused by LPS. Ind injected IP but not ICV significantly attenuated the LPS-induced anorexia. The drowsiness caused by LPS was completely inhibited by Ind injected IP and partially inhibited by Ind administered ICV. These results are interpreted to indicate that LPS induces hyperthermia in the chicken by activating a PG system in the brain. Peripheral PGs appear to be involved in the anorectic response to LPS, whereas drowsiness caused by LPS may involve both peripheral and central PGs. These data are consistent with the hypothesis that multiple PG systems are activated during the acute-phase response, which may explain the dissociation between mechanisms controlling the behavioral and physiological responses to infection.
Animals↗
Sickness behavior in birds caused by peripheral or central injection of endotoxin.
Recent evidence indicates that many of the physiologic, metabolic, and behavioral responses that accompany infection in mammals are important for maintaining homeostasis and promoting recovery. In the present report, we have extended this concept to birds by demonstrating that LPS injected IP reduces feed intake, increases somnolence, decreases plasma [Fe] and [Zn], increases plasma [Cu], and elevates plasma corticosterone. To determine if any of these effects could be mediated centrally, LPS was injected intracerebroventricularly (ICV). Whereas peripheral injection of LPS caused a modest increase in body temperature, the hyperthermic effect of LPS injected ICV was intense and long lasting. This hyperthermia following ICV injection of LPS was accompanied by only a transient reduction in food intake and elevation in somnolent activity, with no change in plasma [Fe] or [Zn]. Both peripheral and central injections of LPS increased plasma corticosterone, but the increase caused by peripherally administered LPS was sixfold higher than that caused by LPS injected centrally. Collectively, these data show that chickens respond to both peripheral and central injections of endotoxin by reducing food consumption, increasing somnolence, becoming febrile, and elevating plasma corticosterone. However, the magnitude of these responses depends upon whether LPS acts at central or peripheral sites.
Animals↗
Gonadal steroids influence the involvement of arginine vasopressin in social recognition in mice.
Gonadal steroids have been shown to modulate the involvement of vasopressinergic neurotransmission in social recognition in rats. To assess whether the same phenomenon occurs in another species showing sexual dimorphism of vasopressinergic neurons, social recognition was studied in DBA2 male mice. Social recognition was inferred from the reduction in investigation time of a juvenile conspecific when this social stimulus was presented for the second time at different intervening intervals after the initial exposure. Such a reduction occurred when the interval was 20 min or 1 hr but not 2 hr. This effect was stimulus-specific, because it did not occur when a different juvenile was presented on the second exposure. AVP (0.4 micrograms/mouse, SC) injected immediately after the first exposure to the juvenile prolonged social recognition, whereas SC injection of an antagonist of the vasopressor receptors of AVP, dPTyr(Me)AVP (2 micrograms/mouse) impaired it. Compared with intact males, castrated mice spent less time investigating juveniles but were still able to recognize them after a 2-hr interval. However, this recognition was no longer sensitive to dPTyr(Me)AVP. These results confirm that androgen-dependent vasopressinergic transmission modulates social recognition in mice.
Androgens↗
Psychoneuroendocrinology on the move.
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Neuroendocrinology↗
Molecular identification of two types of interleukin-1 receptors in the murine pituitary gland.
The present study was carried out to characterize interleukin-1 (IL-1) receptors on murine pituitary cells. Receptor autoradiography confirmed the existence of binding sites for IL-1 alpha in the murine adenohypophysis, but not in the neural or intermediate lobes. Specific binding of IL-1 to isolated pituitary membranes revealed a Kd of 0.9 nM with a Bmax of 37 fmol/mg protein. To examine the possibility that the adenohypophysis synthesizes a receptor for IL-1, immunocytochemistry experiments with a specific monoclonal antibody against the type I receptor revealed the existence of this protein in only the adenohypophysis. Identity of the type I IL-1 receptor was similar to that found on T cells as determined by: 1) amplification of the predicted 619 bp fragment spanning the cytoplasmic, transmembrane and extracellular domains from RNA of pituitary and T cell origin, as well as clonal AtT-20 pituitary cells, and 2) restriction fragment analysis and sequencing of the amplified cDNAs. The pituitary gland and AtT-20 cells also expressed transcripts for the newly identified type II receptor for IL-1 as assessed by amplification of a specific 325 bp fragment, restriction fragment analysis and nucleotide sequencing, and these transcripts were similar to those found on B lymphocytes. These data identify two different forms of the IL-1 receptor in both normal and transformed pituitary cells and establish that these receptors are similar at the molecular level to those first identified on T and B lymphocytes.
Animals↗
Somatolactogens, somatomedins, and immunity.
The neuroendocrine and immune systems participate as active partners in host homeostatic and defense mechanisms. This partnership involves a complex intercommunication system employing an array of shared ligands and receptors. Hormones of the somatolactogen family have marked influences on immune events in vivo, including the maintenance of lymphoid tissue cellularity, the promotion of DNA synthesis in these tissues, and the stimulation of a number of immune effector mechanisms. Both growth hormone and prolactin function to promote erythropoiesis and DNA synthesis in bone marrow precursors. Our results have shown that the somatolactogens and a member of the somatomedin family, IGF-I, are particularly effective in modulating the effector functions in phagocytic cells, including the production of reactive oxygen intermediates and tumor necrosis factor-alpha and the oxygen-dependent killing of bacteria. Evidence indicating a role of IGF-I in modulating immune functions is more recent but nonetheless compelling. Accumulated data suggest that somatolactogenic hormones, as well as one member of the somatomedins, are produced by cells of the immune system and can regulate local immune events. Although the molecular mechanisms by which the somatolactogens and somatomedins exert their effects on immune tissues are only now being explored, the pleiotropic nature of these effects suggests that these hormones participate at endocrine, paracrine, and perhaps autocrine sites of action.
Animals↗
Different receptor mechanisms mediate the pyrogenic and behavioral effects of interleukin 1.
Interleukin 1 (IL-1) is a cytokine released during immune activation that mediates the host's response to infection and inflammation. Peripheral and central injections of IL-1 induce fever and sickness behavior, including decreased food motivation and reduced interest in social activities. To determine the receptor mechanisms responsible for these effects, rats were injected with IL-1 receptor antagonist (IL-1ra), an endogenous cytokine that acts as a pure antagonist of IL-1 receptors. IL-1ra blocked the increased body temperature and oxygen consumption induced by injection of recombinant human IL-1 only when both cytokines were administered i.p. In contrast, i.p. or intracerebroventricular administration of IL-1ra blocked the depressive effect of IL-1 beta on food-motivated behavior and social exploration when this cytokine was administered by the same route as the antagonist. In addition, intracerebroventricular IL-1ra blocked the reduction in social exploration produced by i.p. IL-1 beta but had only partial antagonist effects on the decrease in food-motivated behavior induced by i.p. IL-1 beta. In each case, the dose of IL-1ra was 100- to 1000-fold in excess of the biologically active dose of IL-1. These results suggest that the receptor mechanisms that mediate the behavioral and pyrogenic effects of IL-1 are heterogeneous.
Animals↗
Effects of lipopolysaccharide on food-motivated behavior in the rat are not blocked by an interleukin-1 receptor antagonist.
To investigate the role of interleukin-1 (IL-1) in the decrease in food-motivated behavior after peripheral administration of lipopolysaccharide (LPS), rats trained to press a lever for food on a fixed ratio 10 schedule were pre-treated with a recombinant human IL-1 receptor antagonist (IL-1ra). This endogenous cytokine has been shown to block most of the inflammatory and immune effects of IL-1 both in vitro and in vivo. Intraperitoneal (i.p.) injection of LPS (400 micrograms/kg) decreased operant responding for food to 30-60% of baseline for 1-4 h. Response rates gradually recovered, but were still below control levels 8 and 24 h post-injection. Neither i.p. (8 mg/kg) nor intracerebroventricular (288 micrograms/kg) administration of IL-1ra blocked the effects of peripherally administered LPS on food-motivated behavior. These results suggest that the effects of LPS on this behavior are not mediated by the release of IL-1.
Animals↗
Mechanisms of the behavioral effects of interleukin 1. Role of prostaglandins and CRF.
Sickness behavior induced by IL-1 can be assessed quantitatively by measuring disruption of schedule-controlled behavior and loss of interest in social activities displayed by rats or mice injected peripherally or centrally with this monokine. These effects are mediated via the release of prostaglandins since they are blocked by the prostaglandin synthesis inhibitors indomethacin and piroxicam. They do not depend, however, on the central release of CRF, since they are not altered by central administration of either CRF or the specific antagonist of CRF receptors.
Animals↗
Effects of interleukin-1 receptor antagonist on the behavioral effects of lipopolysaccharide in rat.
To investigate the role of interleukin-1 (IL-1) in lipopolysaccharide (LPS)-induced sickness behavior, rats were injected with recombinant human interleukin-1 receptor antagonist (IL-1ra), an endogenous cytokine able to block most of the biological effects of IL-1 both in vivo and in vitro. Intraperitoneal injection of IL-1ra (3 mg/rat) attenuated the depressive effect of LPS (250 micrograms/kg) on social exploration and body weight when both treatments were injected peripherally. Intracerebroventricular injection of IL-1ra (60 micrograms/rat) did not block the effects of peripherally injected LPS. These data indicate that the peripherally mediated effects of IL-1 account for a significant part of LPS-induced sickness behavior.
Animals↗
Chronic intracerebral infusions of vasopressin and vasopressin antagonist modulate social recognition in rat.
To assess the role of androgen-dependent brain vasopressinergic transmission in the modulation of social recognition, castrated male rats which are deficient in vasopressin were implanted intracerebroventricularly with an Accurel collodion mini-device containing 10 micrograms vasopressin (AVP) whereas intact male rats were implanted with a similar device containing 50 micrograms of 1-deaminopenicillamine 2-O-methyltyrosine arginine vasopressin (dPTyr(Me)AVP), a specific antagonist of the vasopressor like receptors of vasopressin. Control rats in each experimental group were implanted with an Accurel device containing water. Castrated rats treated with AVP explored familiar juvenile conspecifics in the same manner as intact male rats. Conversely, intact male rats treated with dPTyr(Me)AVP explored familiar juveniles in the same manner as castrated male rats. These results confirm the role of androgen-dependent vasopressinergic neurotransmission in social recognition.
Analysis of Variance↗
The macrophage-activating properties of growth hormone.
1. We compared the ability of growth hormone (GH) and a well-characterized macrophage-activating factor, interferon-gamma (IFN-gamma) to activate highly purified populations of alveolar macrophages. Both GH and IFN-gamma primed macrophages triggered with opsonized zymosan to secrete superoxide anion (O2-) in vitro, but IFN-gamma was effective at a 40-fold lower concentration. Antibody blocking studies demonstrated that the priming activity of GH was independent of IFN-gamma, and the activity of IFN-gamma was distinct from that of GH. 2. Both IFN-gamma and GH increased the capability of macrophages to kill Pasteurella multocida in vitro. 3. Hypophysectomized rats challenged with Salmonella typhimurium were significantly protected by injections of either GH or recombinant rat IFN-gamma in vivo compared to vehicle-treated controls, and the protective effect of GH was increased by incorporation into liposomes. 4. Insulin-like growth factor-I (IGF-I) also primed alveolar macrophages in vitro, which is consistent with the idea that the protective effects of GH in vivo might be mediated by augmenting the synthesis of IGF-I. These data support the concept of reciprocal systems of communication between the neuroendocrine and immune systems.
Animals↗