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R Dantzer

Publications and source records attributed to R Dantzer.

At least 37 records · Page 2Linked to original sources
PubMed1997

Central interleukin-1 receptors as mediators of sickness.

These data establish that cytokines, such as IL-1, can act on specific receptors within the brain to induce many symptoms of sickness. A number of inflammatory stimuli in the periphery can activate both the transcription and translation of IL-1 within the central nervous system. It will now be important to determine if similar central IL-1 pathways are activated during SLE and whether these central inflammatory cytokines are involved in the neurologic complications that often accompany this disease.

Animals↗
PubMed1997

IL-4 and insulin-like growth factor-I inhibit the decline in Bcl-2 and promote the survival of IL-3-deprived myeloid progenitors.

The proto-oncogene product Bcl-2 regulates cell survival in both the immune and central nervous systems. We withdrew growth factors from IL-3-dependent murine myeloid progenitor cells (factor dependent cell progenitors (FDCP)) and measured a time-dependent 80% reduction in endogenous expression of Bcl-2. This decline in Bcl-2 is directly associated with a fourfold increase in the apoptotic population after 12 h and an eightfold increase after 24 h. Since IL-4 and insulin-like growth factor-I (IGF-I) regulate myeloid cell growth, we used IL-3-deprived FDCP cells to determine whether IL-4 and IGF-I maintain Bcl-2 expression and prevent apoptosis. We demonstrate that IL-4, like IGF-I and IL-3, promotes survival of FDCP cells by reducing the apoptotic population. Flow cytometric measurement of intracellular Bcl-2 established that IL-4 and IGF-I maintain 10-fold higher levels of Bcl-2 than in IL-3-deprived cells. Similarly, Western analysis of Bcl-2 in lysates of IL-3-deprived myeloid progenitors confirmed that both IL-4 and IGF-I share with IL-3 the ability to maintain intact Bcl-2 protein. However, IL-4 and IGF-I do not change expression of the apoptotic inducer, Bax, although they maintain high levels of Bcl-2 that coimmunoprecipitate with Bax. Collectively, these data demonstrate that IL-4 and IGF-I, like IL-3, inhibit apoptosis in myeloid progenitors and maintain high levels of Bcl-2/Bax heterodimers, suggesting that Bcl-2 is a critical convergence point in the signaling pathways used by IL-4 and IGF-I.

Animals↗
PubMed1997

Activation of phosphatidylinositol 3'-kinase by insulin-like growth factor-I rescues promyeloid cells from apoptosis and permits their differentiation into granulocytes.

Insulin-like growth factor-I (IGF-I) promotes cell division and prevents programmed cell death in hemopoietic progenitors. Human HL-60 promyeloid cells differentiate toward the granulocytic lineage when stimulated with retinoic acid (RA) in serum-containing medium. When deprived of serum, however, we found that these cells differentiate poorly in the presence of RA, as assessed by expression of the alpha subunit of the beta2 integrin heterodimer, CD11b/CD18. However, when IGF-I is added to RA-treated cells, the proportion of CD11b-positive cells increases to a level similar to that in RA-treated cells cultured in serum-containing medium. Cells treated with RA alone not only differentiate poorly but also undergo apoptosis, as assessed by flow cytometry using propidium iodide and HO33342. In serum-free medium, one-third of RA-treated cells become apoptotic compared with only 5% apoptotic cells in the absence of RA. However, addition of IGF-I to RA-treated cells prevents the appearance of this apoptotic population and increases phosphatidylinositol 3'-kinase (PI 3-kinase) activity by fivefold. Wortmannin, a PI 3-kinase inhibitor, potently decreases this IGF-I-induced lipid kinase activity, blocks the ability of IGF-I to prevent apoptosis, and inhibits IGF-I-enhanced CD11b expression. These data demonstrate that IGF-I acts on RA-treated progenitors to promote their differentiation along the granulocytic lineage. IGF-I acts by rescuing these cells from apoptotic cell death via a downstream pathway that is dependent upon PI 3-kinase.

Apoptosis↗
PubMed1997

C3H/HeJ mice are refractory to lipopolysaccharide in the brain.

C3H/HeJ mice are refractory to lipolysaccharide (LPS) in the periphery, primarily because their macrophages do not respond to LPS and produce pro-inflammatory cytokines such as interleukin-1 (IL-1). To determine if they are also refractory to LPS in the brain, behavior of C3H/HeJ mice was compared to LPS-sensitive C3H/HeOuJ mice following intracerebroventricular (I.C.V.) injection of LPS. Whereas ICV injection of LPS (3-1000 ng/mouse) depressed social behavior, food motivation, object investigation and body weight in C3H/HeOuJ mice, C3H/HeJ mice were entirely refractory to LPS in the brain. To determine if the refractoriness of C3H/HeJ mice could result from an inability to synthesize IL-1, recombinant murine IL-1 was injected I.C.V. in both mouse strains. Central administration of IL-1 (1 or 2 ng/mouse) depressed social behavior and body weight similarly in both endotoxin-sensitive C3H/HeOuJ mice and endotoxin-resistant C3H/HeJ mice. That C3H/HeJ mice were refractory to the behavioral effects of central LPS, but not IL-1, suggests that microglia (and other cells in the brain) in C3H/HeJ mice have in common with peripheral macrophages, an inability to respond to LPS and produce cytokines. These data suggest a genetic basis for sickness behavior and demonstrate the utility of preventing central cytokine production in manipulating LPS-induced sickness behavior.

Animals↗
PubMed1997

Hypersensitivity of lurcher mutant mice to the depressing effects of lipopolysaccharide and interleukin-1 on behaviour.

Lurcher mutant mice are characterized by a fast and almost total loss of olivocerebellar neurones during the first postnatal month, associated with a chronic inflammatory state. To test their brain sensitivity to proinflammatory cytokines, we assessed the behavioural responses of adult male Lurcher and wild type to an i.p. or i.c.v. injection of rat recombinant IL-1 beta, and lipopolysaccharide (LPS). IL-1 beta (15 micrograms kg-1, i.p. or 1 ng i.c.v.) decreased social exploration measured 2, 4 and 6 h later, and this decrease was significantly more pronounced in Lurcher than in wild type mice. LPS (60 micrograms kg-1, i.p. or 5 ng i.c.v.) decreased social exploration measured 2 and 4 h later, and this effect was also significantly more marked in Lurcher than in wild type mice. These results suggest that the chronic inflammatory state which characterizes Lurcher mice renders these animals more sensitive to the effects of cytokines such as IL-1 beta and LPS. This difference may be due to the higher reactivity of brain macrophages and glial cells to LPS and IL-1 in Lurcher mice than in wild type.

Animals↗
PubMed1997

Differential effects of lipopolysaccharide on pup retrieving and nest building in lactating mice.

Behavioral symptoms of sickness that develop in response to lipopolysaccharide (LPS) and proinflammatory cytokines include depressed locomotion, anorexia, and reduced social activities. The way maternal behavior is affected in response to cytokines has, however, not yet been investigated. We checked that lactating mice are sensitive to LPS by showing that LPS- (400 microg/kg, ip) injected mice ate and drank less than saline-injected mothers and displayed a decreased rectal temperature. At an ambient temperature of 22 degrees C, nest building was significantly decreased in LPS-treated mothers compared to saline-treated animals, whereas pup retrieving, while slower, was still present and globally as efficient as for saline-treated mice. In a second experiment, dams were either injected with physiological saline or LPS but were also exposed to a cold ambient temperature (6 degrees C) or kept in standard external condition (22 degrees C). LPS-treated mice exposed to cold expressed not only pup-retrieving but also nest-building activity. These differential results indicate that the behavioral expression of LPS-induced sickness depends on the priority of the behavior under consideration.

Animals↗
PubMed1997

Differential effect of lipopolysaccharide on food hoarding behavior and food consumption in rats.

Experimental studies assessing the suppressing effect of lipopolysaccharide (LPS) on feeding behavior have focused exclusively on the ingestive component of this behaviour without taking into account its appetitive component. The appetitive sequence of feeding behavior regroups activities animals engage in to gain access to food without necessarily eating it. The objective of the present study was to compare the effects of LPS on food intake and food hoarding. Rats were given the possibility to access food during a 30-min daily session in an apparatus consisting of a cage connected to an alley with free food at its end. Subjects were tested under different motivational levels for food hoarding: a first group (FS) received a food supplement to maintain stable body weight while a second group (noFS) did not receive such a supplement. LPS (250 micrograms/kg i.p.) dramatically decreased total food intake in rats from both groups whereas food hoarding was much less affected in LPS-treated rats from the noFS group. This expression of a still salient secondary motivation in LPS-treated rats which did not receive any food supplement can be interpreted to suggest the expression of an anticipatory feeding behavior along with a reduced immediate appetite. In addition, LPS had no effect, in rats from the noFS group, on the amount of food eaten after transport to the refuge. LPS-treated animals still appear to be able to adjust their defensive behavioral strategies with regard to their needs and capacities. These findings support the adaptive value of the behavioral changes displayed by LPS-treated animals.

Animals↗
PubMed1997

Defect in interleukin-1beta secretion prevents sickness behavior in C3H/HeJ mice.

To examine the role of interleukin-1beta (IL-1beta) in mediating sickness, we studied the effects of lipopolysaccharide (LPS) and IL-1beta on social behavior in endotoxin-responsive C3H/HeOuJ (OuJ) mice and endotoxin-resistant C3H/HeJ (HeJ) mice. Whereas LPS (1, 10 and 100 microg) depressed social behavior and body weight compared to saline in OuJ mice, in HeJ mice it did not. To determine if the refractoriness of HeJ mice to the behavioral effects of LPS was related to secretion of IL-1beta, in a second study, HeJ and OuJ mice were injected IP with LPS (10 microg) and plasma concentration of IL-1beta was determined postinjection. At 4 h postinjection, the plasma concentration of IL-1beta was increased by LPS in OuJ mice, but not in HeJ mice. The increase in plasma IL-1beta in OuJ mice corresponded to the maximal depression in social behavior. To further verify that HeJ mice are refractory to the behavioral effects of LPS because they fail to respond and produce cytokines, the social behavior of HeJ and OuJ mice injected IP with recombinant murine IL-1beta (0, 50, 100, or 200 ng) was compared. As anticipated, exogenous IL-1beta depressed social behavior similarly in endotoxin-responsive OuJ mice and endotoxin-resistant HeJ mice. These data indicate that a genetic mutation in HeJ mice that prevents LPS-induced synthesis of cytokines also renders HeJ mice refractory to the behavioral effects of LPS.

Animals↗
PubMed1997

Cholecystokinin receptors do not mediate the behavioral effects of lipopolysaccharide in mice.

To test the possible role of cholecystokinin (CCK) in the decrease of social exploration induced by intraperitoneal (IP) injection of lipopolysaccharide (LPS, 100 microg/kg), mice were pretreated with IP or intracerebroventricular (ICV) injection of the CCKA receptor antagonist L-364,718 (3 mg/kg and 10 microg/kg, respectively) and the CCKB receptor antagonist L-365,260 (1 mg/kg and 10 microg/kg, respectively). L-364,718 and L-365,260 did not alter LPS-induced decrease in social investigation, whatever the route of administration, suggesting that endogenous cholecystokinin does not mediate the effect of proinflammatory cytokines on social exploration in mice.

Animals↗
PubMed1997

Hormones, lymphohemopoietic cytokines and the neuroimmune axis.

The classical distinction between hormones and cytokines has become increasingly obscure with the realization that homeostatic responses to infection involve coordinated changes in both the neuroendocrine and immune systems. The hypothesis that these systems communicate with one another is supported by the ever-accruing demonstrations of a shared molecular network of ligands and receptors. For instance, leukocytes express receptors for hormones and these receptors modulate diverse biological activities such as the growth, differentiation and effector functions. Leukocyte lineages also synthesize and secrete hormones, such as insulin-like growth factor-I (IGF-I), in response to both growth hormone (GH) and also to cytokines such as tumor necrosis factor-alpha (TNF-alpha). Since hormones share intracellular signaling substrates and biological activities with classical lymphohemopoietic cytokines, neuroendocrine and immune tissues share a common molecular language. The physiological significance of this shared molecular framework is that these homeostatic systems can intercommunicate. One important example of this interaction is the mechanism by which bacterial lipopolysaccharide, by eliciting a pro-inflammatory cytokine cascade from activated leukocytes, modulate pituitary GH secretion as well as other CNS-controlled behavioral and metabolic events. This article reviews the cellular and molecular basis for this communication system and proposes novel mechanisms by which neuroendocrine-immune interactions converge to modulate disease resistance, metabolism and growth.

Animals↗
PubMed1997

Central mediation of the effects of interleukin-1 on social exploration and body weight in mice.

To study the role of central IL-1 receptors in the effects of recombinant human IL-1 beta (IL-1 beta) on behavior and body weight, intracerebroventricular (i.c.v.) injection of the specific antagonist of IL-1 receptors, IL-1ra, was administered to mice injected intraperitoneally (i.p.) and i.c.v. with various doses of IL-1 beta. Doses of 500 ng i.p. IL-1 beta and 900 pg i.c.v. IL-1 beta induced a comparable decrease in social behavior and loss of body weight. Pretreatment with IL-1ra (1.8 micrograms/mouse, i.c.v.) blocked the effects of i.c.v. IL-1 beta (900 pg/mouse) on social behavior. i.c.v. IL-1ra (3.6 micrograms/mouse) also attenuated the effects of i.p. IL-1 beta (500 ng/mouse) on social behavior and change in body weight, suggesting that the effects of peripheral IL-1 beta are centrally mediated.

Animals↗
PubMed1997

Regulation of cytokine gene expression in the central nervous system by glucocorticoids: mechanisms and functional consequences.

The proinflammatory cytokines which are released by activated accessory immune cells during the course of an infection have profound effects on the brain. These effects include activation of the hypothalamic-pituitary-adrenal axis, fever and behavioral depression. They are mediated by cytokines which are synthesized and released in the brain, in response to peripherally released cytokines. Glucocorticoids have potent regulatory effects on the synthesis of cytokines by activated macrophages and monocytes. These hormones are also able to regulate the synthesis and action of cytokines in the brain, as demonstrated by the sensitizing effects of adrenalectomy and the depressing effects of stress on the increased cytokine and interleukin-1 beta converting enzyme gene expression that occurs in response to lipopolysaccharide in mice. Preliminary experiments indicate that another way glucocorticoids can contribute to down regulation of the IL-1 system is by increasing the expression of the type II IL-1 receptor in the brain. The regulatory effects of glucocorticoids on cytokine expression in the brain have functional consequences, as demonstrated by the enhanced sensitivity of adrenalectomized animals to the behavioral actions of centrally administered LPS and IL-1. The effects of adrenalectomy are inhibited by compensation with a corticosterone implant and they are mimicked by administration of the type II glucocorticoid receptor, RU 38486. The regulatory role of glucocorticoids on the expression and action of cytokines in the brain makes these hormones and their mechanisms of action key targets for therapeutic interventions in psychopathology and neuropathology.

Animals↗
PubMed1997

Systemic capsaicin pretreatment fails to block the decrease in food-motivated behavior induced by lipopolysaccharide and interleukin-1beta.

The physiological and behavioral disturbances observed during an infection can be reproduced by systemic administration of proinflammatory cytokines (e.g., interleukin (IL)-1, IL-6, tumor necrosis factor-alpha) or lipopolysaccharide (LPS), a potent inducer of these cytokines. It is now well established that these molecules induce their effects by acting centrally, however, the mechanisms by which they reach central structures are not clear. We have earlier proposed that the humoral immune message is converted to a central neural activation by the action of cytokines on peripheral terminations of afferent neurons. Subdiaphragmatic vagotomy abolishes several effects of peripherally injected IL-1beta and LPS (e.g., decreased food-motivated behavior and social exploration, central expression of cytokines). To further define the nature of the peripheral fibers implicated in this phenomenon, we used a potent sensory neurotoxin, capsaicin, to selectively destroy C-fiber afferents. Adult rats were injected I.P. with a total dose of 25 mg/kg capsaicin in a series of 10 injections over a 48-h period. Adult mice were injected I.P. with a total dose of 75 mg/kg in a series of seven injections over a 7-day period. Although capsaicin treatment altered visceral chemosensory function, corneal and pain sensitivity, vagal-mediated anorexic effects of cholecystokinin, and depleted levels of substance P in the thoracic spinal cord, it was completely ineffective in blocking the decrease in food-motivated behavior induced by IL-1beta (4 microg/rat I.P. in rats) and LPS (250 microg/kg I.P. in rats and 400 microg/kg I.P. in mice). Thus, other afferents besides capsaicin-sensitive C-fibers appear to be involved in the transduction of cytokine effects during inflammatory and infectious events.

Animals↗
PubMed1997

Central lipopolysaccharide elevates plasma IL-6 concentration by an alpha-adrenoreceptor-mediated mechanism.

High circulating levels of interleukin-6 (IL-6) are evident after intracerebroventricular injection of lipopolysaccharide (LPS). To investigate the pathway of centrally induced IL-6 production, in the present study we evaluated the effects of specific alpha-adrenergic receptor antagonists administered peripherally on IL-6 production and hypertriglyceridemia induced by LPS administered centrally. In the first study, adult male Wistar-Furth rats were injected intracerebroventricularly with LPS. Centrally injected LPS increased plasma IL-6 and triglycerides (TG) in a dose-dependent fashion. To determine if LPS increased plasma IL-6 and TG through an alpha-adrenoreceptor mechanism, rats were pretreated intraperitoneally with either vehicle, phentolamine (alpha 1- and alpha 2-receptor antagonist), prazosin (alpha 1-receptor antagonist), or yohimbine (alpha 2-receptor antagonist). Thirty minutes later, rats were injected intracerebroventricularly with LPS. Whereas prazosin and yohimbine attenuated the increases in plasma IL-6 caused by LPS, phentolamine completely blocked the peripheral effects of central LPS. These data suggest that increased sympathetic activity and subsequent activation of alpha 1- and alpha 2-adrenergic receptors are important for controlling peripheral metabolic and endocrine systems when inflammatory stimuli are present in the brain.

Adrenergic alpha-Antagonists↗
PubMed1997

Regulation of myeloid growth and differentiation by the insulin-like growth factor I receptor.

Flow cytometry was used to examine the expression of type I insulin-like growth factor receptors (IGF-IR) on three types of human hematopoietic cells that represent different stages of myeloid lineage development. Both HL-60 (promyeloid) and U-937 (monocytic) cells express abundant IGF-IR protein (> 79% cells positive for the IGF-IR), whereas KG-1 myeloblasts express negligible levels of IGF-IR (< 1% IGF-IR-positive cells). Exogenous IGF-I, IGF-II, and an IGF-I analog that binds poorly to IGF-binding protein-3 (des-IGF-I) increased DNA synthesis of HL-60 and U-937 cells in a dose-dependent (1-25 ng/ml) fashion by 2- to 4-fold in serum-free medium, whereas KG-1 cells did not respond to any of these growth factors. The IGF-induced increase in proliferation of HL-60 promyeloid cells was inhibited by soluble IGF-binding protein-3 (500 ng/ml) when these cells were stimulated with 10 ng/ml of either IGF-I (53 +/- 8%) or IGF-II (59 +/- 8%), but not with des-IGF-I (3 +/- 1%). In contrast, the anti-IGF-IR monoclonal antibody (mAb; alpha IR-3) inhibited the DNA synthesis caused by 10 ng/ml exogenous IGF-I (67 +/- 6%), IGF-II (72 +/- 8%), and des-IGF-1 (82 +/- 9%). Proliferation of KG-1 myeloblasts, however, was neither stimulated by the IGFs nor inhibited by the anti-IGF-IR mAb. In the absence of exogenous IGF-I, the mAb directed against the IGF-IR significantly suppressed basal DNA synthesis of HL-60 promyeloid (72 +/- 5%) and U-937 monocytic (39 +/- 7%) cells, but did not affect DNA synthesis of KG-1 myeloblasts (8 +/- 1%) compared to an isotype-matched control mAb. Similarly, the alpha IR-3 mAb abrogated vitamin D3-induced differentiation of the HL-60 cells into macrophages in serum-free medium, as assessed by expression of the leucam surface protein, CD11b. As the alpha IR-3 mAb inhibits DNA synthesis in the presence and absence of exogenous IGF-I on receptor-bearing cells, but not IGF-IR-negative cells, these data demonstrate that both endocrine and autocrine IGF-I are potent growth factors in human myeloid cells where expression of the surface receptor, rather than the ligand, is the critical control element. More importantly, these data support the hypothesis that autocrine IGF-I may play a significant role in the differentiation of promyeloid cells into macrophages.

Bone Marrow Cells↗
PubMed1997

Stress and immunity: what have we learned from psychoneuroimmunology?

The old concept that stress depresses immunity must be qualified. There is now evidence that in the same way that different perceptions of stress have different physiological consequences, different ways of coping with stress result in different consequences on immunity, the nature and outcome of which depend on the type of immune response. The mechanisms that are involved in these effects involve neuroendocrine and autonomic pathways. These pathways are actually part of a network of bidirectional interactions between the central nervous system and the immune system, which plays an important role in the physiological regulation of immunity.

Animals↗
PubMed1996

Vagotomy blocks behavioural effects of interleukin-1 injected via the intraperitoneal route but not via other systemic routes.

To test specificity of the involvement of vagal afferents in the communication between the immune system and the brain, sham-operated and vagotomized mice were injected i.p., s.c. or i.v. with physiological saline or interleukin-1 beta (IL-1 beta [symbol: see text] 4 weeks after surgery. Vagotomy attenuated the decrease in social exploration induced by i.p. injection of 300 ng recombinant human IL-1 beta but had no effect when IL-1 beta was injected s.c. (300 ng) or i.v. (500 ng). Vagotomy also attenuated the depression in social investigation induced by i.p. injection of recombinant rat IL-1 beta (IL-1 beta, 1 microgram) but was without effect when 1 microgram IL-1 beta was injected i.v. These results confirm the role of vagal afferent nerves in the transmission of an immune message from the periphery to the brain and show that the vagus nerve only conveys information concerning cytokines injected into the abdominal cavity.

Animals↗