Biomedical subjects

R Dantzer

Publications and source records attributed to R Dantzer.

At least 109 records · Page 6Linked to original sources

PubMed1995

Endogenous glucocorticoids down regulate central effects of interleukin-1 beta on body temperature and behaviour in mice.

Adrenalectomy sensitizes laboratory animals to the pyrogenic and behavioural effects of proinflammatory cytokines. To determine whether these effects are mediated by central sites of action of glucocorticoids, interleukin-1 beta was injected intracerebroventricularly (i.c.v.) in adrenalectomized mice with or without corticosterone supplementation and in mice pretreated i.c.v. with the glucocorticoid type II receptor antagonist RU38486. Adrenalectomized mice were more sensitive to the depressing effects of i.c.v. IL-1 beta on body temperature and social exploration than sham-operated mice. Corticosterone supplementation reversed the increased sensitivity to the low (300 pg/mouse) but not to the high dose (900 pg/mouse) of IL-1 beta. Central administration of RU38486 (0.5-1 microgram/mouse) mimicked the effects of adrenalectomy on behaviour but not on body temperature. These results suggest that endogenous glucocorticoids released in response to IL-1 beta act in the brain to modulate the sensitivity of the cellular targets of this cytokine.

Animals↗

PubMed1995

Differential effects of IL-1ra on sickness behavior and weight loss induced by IL-1 in rats.

Peripheral and central injections of recombinant human interleukin-1 beta (IL-1 beta) have been shown to decrease social exploration and to induce body weight loss in rats. To characterize the receptor mechanisms of these effects, we used as a tool a specific antagonist of the receptors of IL-1, IL-1ra. Intraperitoneal (i.p.) administration of IL-1ra (8 mg/kg) blocked the effect of i.p. injection of IL-1 beta (4 micrograms/rat) on social behaviour but not on body weight. Central administration of IL-1ra (60 micrograms/rat, i.c.v.) abrogated the effects of centrally administered IL-1 beta (30 ng/rat, i.c.v.) on both social behaviour and body weight. Central injection of IL-1ra (4 micrograms/rat, i.c.v.) also attenuated the effects of i.p. administered IL-1 beta (4 micrograms/rat) on social behaviour but not on body weight. These results suggest that the effects of IL-1 beta on social behavior are mediated centrally and that its effect on the loss of body weight involves different receptor mechanisms.

Animals↗

PubMed1995

Pyrogens specifically disrupt the acquisition of a task involving cognitive processing in the rat.

In addition to changes in body temperature and other metabolic and physiological responses corresponding to immune activation, pyrogens can induce profound behavioral changes referred to collectively as sickness behavior. One feature of sickness behavior, sometimes reported in clinical settings, but rarely exposed to experimental analysis, is depressed cognitive functioning. The present series of five experiments sought to demonstrate the existence of specific cognitive deficits in rats, independently of any confounding performance effects of pyrogen injections. The behavioral task used, called autoshaping, consisted of presenting hungry Wistar rats with a stimulus (introduction of a retractable lever) that predicted food delivery. Control rats quickly learned to press the lever, although this response does not influence the probability of food delivery. When pyrogens (250 micrograms/kg lipopolysaccharide, 4 micrograms/rat interleukin-1 beta, or 300 mg/rat yeast) were injected to rats during acquisition of this task, they severely disrupted acquisition while the pyrogen was active. The same treatments were, however, without effect on performance when injected later, when performance had stabilized. It is argued that these results demonstrate specific, performance-independent effects of pyrogens on the cognitive processes needed for the acquisition of this task. The results are discussed in terms of the relationship between these effects and the cytokines induced in the brain by pyrogens, and in terms of the exact nature of the cognitive process likely to be affected.

Animals↗

PubMed1995

Lipopolysaccharide and interleukin-1 depress food-motivated behavior in mice by a vagal-mediated mechanism.

In order to assess the role of vagal nerve afferents in the decrease in food-motivated behavior induced by proinflammatory cytokines, the effects of lipopolysaccharide (LPS, 400 micrograms/kg ip) and recombinant human interleukin-1 beta (IL-1, 750-1500 ng/mouse ip) were tested on nose poke for food in vagotomized and sham-operated mice. Subdiaphragmatic vagotomy attenuated the decrease in response rate induced by IL-1 and LPS. These results suggest that the peripheral immune message is transmitted to the brain via a neural rather than a humoral pathway.

Animals↗

PubMed1995

Stress downregulates lipopolysaccharide-induced expression of proinflammatory cytokines in the spleen, pituitary, and brain of mice.

Mice injected with LPS (10 mu g/mouse, sc) or saline were submitted to a 15-min restraint stress and sacrificed 1 or 2 h later to assess the effect of stress on the induction of interleukin-1beta (IL-1beta) and other proinflammatory cytokines (IL-1alpha, IL-1ra, IL-6, and tumor necrosis factor-alpha) in the spleen, pituitary, hypothalamus, hippocampus, and striatum. LPS-induced cytokine gene expression, as determined by comparative RT-PCR, was lower in stressed than in nonstressed mice. LPS increased plasma and tissue levels of IL-1beta, as determined by ELISA, but this effect was less marked in stressed than in nonstressed mice. These results are discussed in relation to the modulatory effects of glucocorticoids on cytokine production.

Animals↗

PubMed1995

Compared effects of cold ambient temperature and cytokines on macronutrient intake in rats.

To compare the effects of cold and cytokines on spontaneous dietary self-selection, rats (n = 14) were given free access to carbohydrate, protein and fat diets for 4 hours a day. After a 10-day period of habituation to this regimen, they were injected with physiological saline, IL-1 beta (4 micrograms/rat ip) or LPS (83 micrograms/rat ip) or exposed to cold (5 degrees C), the order of treatments being randomized. LPS- and IL-1 beta-treated rats ate less, but ingested relatively more carbohydrate and less protein whereas relative fat intake remained unchanged. In contrast, cold exposed rats slightly increased their food intake but in a non significant manner. They also increased their relative intake of fat but did not change their relative intake of carbohydrate and protein. These results are discussed with respect to the pyrogenic and metabolic effects of cytokines.

Animals↗

PubMed1995

Subdiaphragmatic vagotomy blocks induction of IL-1 beta mRNA in mice brain in response to peripheral LPS.

To test the possibility that the vagus nerve is involved in the communication between the immune system and the brain, we injected sham-operated and vagotomized mice with physiological saline or lipopolysaccharide (LPS; 400 micrograms/kg ip). Vagotomy attenuated LPS-induced depression of general activity measured 2 h after treatment but did not alter the increase in plasma levels of IL-1 beta in response to LPS. In addition, vagotomy abrogated the LPS-induced increase in the levels of transcripts for IL-1 beta, as determined by semiquantitative polymerase chain reaction after reverse transcription, in the hypothalamus and hippocampus, but not in the pituitary of vagotomized mice. This relationship between the effects of vagotomy on the behavioral effects of LPS and the LPS-induced brain expression of IL-1 beta mRNA indicates that vagal afferent fibers play a prominent role in the pathways of communication between the immune system and the brain.

Animals↗

PubMed1995

Corticosterone regulates behavioral effects of lipopolysaccharide and interleukin-1 beta in mice.

The modulatory role of endogenous corticoids in the behavioral effects of lipopolysaccharide (LPS) and recombinant human interleukin-1 beta (IL-1 beta) was studied in mice. Adrenalectomy enhanced the depression of social exploration induced by subcutaneous injection of 200 ng of IL-1 beta or 2 micrograms of LPS. This effect was mimicked by an acute injection of the progesterone antagonist RU-38486 (0.25-1 mg). Chronic replacement with a 15-mg corticosterone pellet abrogated the enhanced susceptibility of adrenalectomized animals to 200 ng of IL-1 beta but had only partial protective effects on their response to 400 ng of IL-1 beta and LPS. These results suggest that the pituitary-adrenal response to cytokines exerts an inhibitory feedback on the cell targets that mediate the behavioral effects of LPS and IL-1 beta.

Adrenalectomy↗

PubMed1995

[Stress theories and the somatization process].

Stress theories aim at understanding pathophysiology of psychosomatic disorders. The first stress theories have been inspired by the principles of homeostasis. They view the response to stressors as a quasi reflex reaction which aims at normalizing disturbed homeostasis. More modern stress theories emphasize the intermediate role of cognitive and behavioural processes in the determinism of neuroendocrine and neurovegetative responses to stressors. Active attempts to control the situation are associated with activation of the sympathetic and adrenal medullary system whereas loss of control is associated with activation of the hypothalamic-pituitary-adrenal axis. Since the functional consequences of the activation of each of these physiological systems are not the same, the risk factors corresponding to each coping strategy are not the same. Whatever their details, physiological and psychobiological stress theories all emphasize the influence of psychic factors on bodily functions. However, mental states do not function independently of bodily functions. In the case of the influences of stress on immunity for instance, it has been shown that these influences represent the counterpart of feedback regulatory mechanisms in which the ability of the brain to regulate immune responses depends on the capacity of the immune system to influence brain functions. Activation of the immune system during infection or inflammation is accompanied by profound metabolic, neuroendocrine and behavioural changes which are mediated by the effects of immune products known as cytokines on brain cell targets. In view of the reciprocal relationships between peripheral organic systems and the brain, a purely psychosomatic view, from the psyche to the soma, is therefore no longer tenable. In addition, biological accounts of somatization processes run into the risk of minimizing the importance of perception and representation of somatic symptoms. Amplification of somatic symptoms is a common feature of neuroticism or negative affectivity and it bears no relationship with objective pathology. In order to understand somatization processes, there is therefore a need to study how the brain processes information it receives from the body and the way this information competes with information from the external environment.

Adaptation, Psychological↗

PubMed1994

A behaviorally active dose of lipopolysaccharide increases sensory neuropeptides levels in mouse spinal cord.

To assess whether peripheral immune stimuli activate sensory afferents at behaviorally active doses, we measured the effects of lipopolysaccharide (LPS) on the levels of sensory neuropeptides in the spinal cord. LPS (10 micrograms/mouse i.p.) increased the levels of substance P, neurokinin A, and calcitonin gene-related peptide in the spinal cord, the maximum being observed 1 hr post-injection. Pretreatment with indomethacin at a dose (5 mg/kg i.p.) which completely blocked the decrease in food-motivated behavior induced by LPS abrogated this effect.

Animals↗

PubMed1994

Ethological study of the effects of tetrahydroaminoacridine (THA) on social recognition in rats.

Two major difficulties confront ethopharmacological investigations on cognitive abilities such as social recognition in drug-treated animals involved in free social interactions. The first concerns the choice of the most relevant behaviours, those reflecting the cognitive abilities attributed to the animals and assessing the specificity of the drug activity, and those reflecting non-specific drug effects. The second refers to the experimenter's awareness that in contrast to physical objects, social stimuli respond to drug-treated subjects and that their own level of responsiveness may influence the changes of drug-treated subjects' social interest. In addition, their contribution may vary according to the different treatments the drug-treated subjects receive. In examining the effects of tetrahydroaminoacridine (THA) at doses of 0.3, 1 and 3 mg/kg on the ability of adult male rats to recognize previously encountered conspecifics, we attempted to take into consideration such difficulties. A detailed behavioural profile of drug-treated rats was reported to separate specific from non-specific effects of THA. In addition, rats were assigned an index of responsibility for contact which takes into account the interactive dimension of each dyad and allows relevant comparisons between different treatments. The doses of THA which were found to decrease the duration of exploration of a familiar juvenile were also found to decrease the number of contacts initiated by the drug-treated subjects. THA induced a relative increase in body care by comparison to saline treatment. However, it had no effect of locomotor activity and rearing of the subjects. These findings enable dissociation of the effects of THA on cognitive versus non-cognitive processes.

Aging↗

PubMed1994

Reduction in food and water intake induced by microinjection of interleukin-1 beta in the ventromedial hypothalamus of the rat.

Interleukin-1 (IL-1) is a cytokine which is released during immune activation and mediates some of the host's responses to infection and inflammation. Increasing evidence suggests that it also has a role as an intrinsic neuromodulator in the central nervous system. We report here that microinjections of 5 and 30 ng (286 fmol and 1.71 pmol) of recombinant human IL-1 beta in the ventromedial nucleus of the hypothalamus (VMH) of adult male rats time- and dose-dependently induce anorexia and weight loss in two experimental paradigms: rats allowed free-access to food and water and food-restricted rats trained to press a lever for food on a fixed ratio 10 schedule. IL-1 beta (5 ng) diminished food and water consumption by 45 and 30%, respectively, and decreased body weight for at least 24 h postinjection in rats fed ad lib. These effects were more severe and lasted at least 48 h after infusion of the larger dose of 30 ng. The IL-1 beta-induced anorexia and weight loss were neither as large nor as long-lasting in food-restricted rats. Operant responding for food was decreased 2-4 h postinfusion of 5 ng IL-1 beta and 2-8 h after 30 ng IL-1 beta, but in both cases returned to baseline within 24 h. Body weight was decreased compared to saline injections from 4 to 24 h postinfusion. Nevertheless, when allowed to eat ad lib for the 24 h immediately following the behavioral testing, body weight returned to control (5 ng) or near control levels (30 ng).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Immunology discovers physiology.

Not so long ago, it was believed that the brain is totally devoid of immunologic reactions, that cytokines derived from activated leukocytes serve only as communication molecules between leukocytes and that the immune system is regulated solely by intrinsic mechanisms. One by one, these old-time, traditional views have fallen by the wayside as neuroscientists, endocrinologists and pharmacologists have begun to explore immunology. The old view was that the immune system is autonomous because it neither affects nor is it affected by other physiologic systems. The new view is that cells of the immune system are inextricably linked with other physiological systems, including the neuroendocrine, cardiovascular, reproductive and central nervous systems (CNS). Changes in one system evoke changes in the other, and it is likely that communication loops have evolved between cells of the immune system and those of other tissues to coordinate and regulate functional activities aimed at preserving homeostasis during inflammation. The integrated view of immunophysiologists that cells of the immune system interact with the entire body, rather than existing as a separate physiologic system that operates autonomously, should help to unravel a number of mysteries in immunoregulation, such as the well-recognized redundant and pleiotropic properties of cytokines. Unfortunately, very few of these ideas have been incorporated into studying immunity of domestic animals. A complete understanding of immunobiology will be achieved only after this new field of immunophysiology is integrated into current immunological thinking.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Expression of type I and type II interleukin-1 receptors in mouse brain.

Although binding sites for IL-1 have been identified in the mouse brain, it is still unknown whether these binding sites correspond to the type I or type II IL-1 receptor. Quantitative autoradiography was used to confirm the presence of specific binding sites for radiolabelled recombinant human IL-1 alpha (125I-HuIL-1 alpha) in the brain of DBA/2 mice. IL-1 binding was highest in the dentate gyrus, consisting of a single class of high affinity binding sites with a Kd of 0.1 nM and a Bmax of 57 fmol/mg protein. A similar Kd of 0.2 nM was obtained using isolated membranes from the whole hippocampus, although the number of binding sites was lower (2 fmol/mg protein). Affinity cross-linking of 125I-Hu-IL-1 alpha to hippocampal membranes revealed the existence of two types of IL-1 receptor proteins, consistent with the sizes of the type I (85 kD) and type II (60 kD) IL-1 receptor. Oligonucleotide probes were then synthesized and used in RT-PCR followed by Southern blotting to show that the whole brain expresses transcripts for both the type I and type II IL-1 receptors. The murine neuroblastoma cell line, C1300, expresses type I rather than type II IL-1 receptor mRNA. The type I receptor protein can be identified by flow cytometry on the membrane of the C1300 neuronal cell line using indirect immunofluorescence with a rat anti-mouse type I IL-1 receptor MoAb. These data show that mouse brain expresses both type I and type II IL-1 receptor mRNA and proteins and offer further support to the idea that type I IL-1 receptors are synthesized and expressed by neurons.

Animals↗

PubMed1994

Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice.

The reverse transcription polymerase chain reaction (RT-PCR) was used to assess the induction of mRNA of the proinflammatory cytokines IL-1 beta, IL-6 and TNF alpha in the spleen, pituitary, hypothalamus and hippocampus of mice after an intraperitoneal injection of lipopolysaccharide (LPS, 10 micrograms/mouse). The kinetics of cytokine gene expression induced by peripheral LPS in the pituitary and brain structures were different from that observed in the spleen. For IL-1 beta the dose-response curve was also measured and also found to be different. These results support the idea that one pathway by which peripheral immune stimuli affect brain functions includes local synthesis of proinflammatory cytokines in certain brain structures.

Animals↗

PubMed1994

Synergy between tumor necrosis factor alpha and interleukin-1 in the induction of sickness behavior in mice.

Like interleukin-1, recombinant human tumor necrosis factor alpha (TNF alpha) has been found to decrease social exploration and induce weight loss in mice in a dose and time-dependent manner. The present study was carried out to study the interaction between these two cytokines. Mice were injected IP with subthreshold doses of TNF alpha (2.5 micrograms/mouse) and IL-1 beta (50 ng/mouse). Social exploration was decreased 2 and 4 h after injection of TNF and IL-1, but body weight was not affected. Subthreshold doses of TNF alpha (90 ng/mouse) and IL-1 beta (100 pg/mouse) were also injected intracerebroventricularly (ICV). Social exploration was decreased 1.5 and 3 h after injections of the two cytokines and body weight was decreased for 6 h. To test the possibility of central induction of IL-1 by TNF alpha, mice pretreated with IL-1 receptor antagonist (IL-1ra, 1.8 micrograms/mouse, ICV) were injected with 90 ng TNF alpha. Pretreatment with IL-1ra antagonized the depressive effect of TNF alpha on behavior, but had no effect on weight loss induced by this cytokine. These results suggest that TNF alpha-induced behavioral alterations are mediated by endogenously released IL-1, whereas metabolic changes are dependent on the release of other cytokines.

Animals↗

PubMed1994

Reduction in superoxide anion secretion and bactericidal activity of neutrophils from aged rats: reversal by the combination of gamma interferon and growth hormone.

Polymorphonuclear neutrophils (PMN) from bone marrow of 24-month-old rats kill Escherichia coli less efficiently than PMN from 3-month-old rats. Secretion of O2- and killing of E. coli by PMN from both young and old rats can be significantly augmented by preincubation with either 250 U of gamma interferon (IFN-gamma) or 250 ng of growth hormone (GH) per ml. This priming is specific, because neutralizing monoclonal antibodies against either IFN-gamma or GH completely abrogate the enhanced O2- secretion by PMN from young rats. However, in contrast to PMN from young rats, PMN from aged rats are not primed to kill E. coli by 10-fold-lower concentrations of either IFN-gamma (25 U/ml) or GH (25 ng/ml). To explore the mechanism for the reduction in bacterial killing by PMN from old rats, a syngeneic GH-secreting pituitary cell line (GH3) was implanted in vivo. PMN from GH3-treated aged rats, but not control aged rats, could now be primed in vitro for O2- secretion by IFN-gamma (25 U/ml). Although PMN from aged rats do not respond to the lower doses of either IFN-gamma or GH, the combination of both reagents totally restores the ability of PMN to secrete O2- and to kill E. coli. This synergistic priming is observed with PMN from aged rats, but not with those from young rats, and can be detected when both reagents are added simultaneously or when they are added in either sequence. Furthermore, addition of a monoclonal antibody against either IFN-gamma or GH abrogates the synergism of these two molecules. Collectively, these data identify an important alteration in myeloid cells from aged rodents by showing that their PMN are intrinsically unable to respond to low concentrations of IFN-gamma by secreting O2- and killing bacteria. The results also define a previously unrecognized synergism in PMN from aged animals by showing that GH synergizes with IFN-gamma both in vivo and in vitro to restore these suppressed responses.

Aging↗

PubMed1994

Competitive reverse transcriptase-polymerase chain reaction using a synthetic internal RNA standard to quantitate transcripts for leukocyte-derived hormones.

Leukocytes synthesize a variety of hormones that were once thought to be unique products of endocrine tissues. Understanding the regulation of leukocyte-derived hormone synthesis requires an accurate means for measuring steady-state expression of specific mRNA transcripts. Here we describe a competitive reverse transcriptase-polymerase chain reaction (RT-PCR) technique to accurately quantitate macrophage-derived insulin-like growth factor-I (IGF-I) mRNA, and demonstrate the utility of this approach for measuring expression of leukocyte-derived hormone transcripts. A riboprobe was constructed to generate approximately 1 kb of synthetic competitor IGF-I RNA (exons 1 and 3-6) that differed from cellular IGF-I RNA by insertion of 122 bp of beta-actin RNA. One set of oligonucleotide primers could thus be used to simultaneously reverse transcribe and amplify both 144 bp of cellular (exons 3 and 4) and 266 bp of competitor IGF-I RNA. Densitometric scanning of the PAGE-separated PCR products revealed that the ratio of competitor to cellular amplified DNA bore a linear relationship (r2 > or = 0.98) to the amount of competitor RNA for both rat liver and splenocytes. However, rat liver contained 104 x 10(6) IGF-I molecules per microgram of total cellular RNA compared to only 2 x 10(6) IGF-I molecules for splenocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗