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R Dantzer

Publications and source records attributed to R Dantzer.

At least 19 recordsLinked to original sources
PubMed2000

Developmental expression of insulin receptor substrate-2 during dimethylsulfoxide-induced differentiation of human HL-60 cells.

Insulin receptor substrate-2 (IRS-2) is phosphorylated on tyrosine by a number of cytokine receptors and is implicated in the activation of phosphatidylinositol 3'-kinase (PI3-kinase). Here, we demonstrate that induction of granulocytic differentiation of human promyeloid HL-60 cells leads to an increase in the amount of IRS-2 that is phosphorylated in response to insulin-like growth factor (IGF)-I. Although PI3-kinase is often activated following interaction with IRS-1, we could not detect IRS-1 protein, IRS-1 mRNA, or IRS-1-precipitable PI3-kinase enzymatic activity. However, PI3-kinase activity that was coimmunoprecipitated with either anti-phosphotyrosine or anti-IRS-2 following IGF-I stimulation was increased 100-fold. Heightened tyrosine phosphorylation of IRS-2 during granulocytic differentiation was not caused by an increase in expression of the tyrosine kinase IGF-I receptor, as measured by the amount of both the alpha- and beta-subunits. Instead, immunoblotting experiments with an Ab to IRS-2 revealed that induction of granulocytic differentiation caused a large increase in IRS-2, and this occurred in the absence of detectable IRS-1 protein. These IRS-2-positive cells could not differentiate into more mature myeloid cells in serum-free medium unless IGF-I was added. These data are consistent with a model of granulocytic differentiation that requires at least two signals, the first of which leads to an increase in the cytoplasmic pool of IRS-2 protein and a second molecule that acts to tyrosine phosphorylate IRS-2 and enhance granulocytic differentiation.

Cell Differentiation↗
PubMed2000

Cholecystokinin receptors do not mediate the suppression of food-motivated behavior by lipopolysaccharide and interleukin-1 beta in mice.

During the course of an infection, profound metabolic and behavioral changes are observed. The resulting decrease in food intake can be reproduced by administration of lipopolysaccharide (LPS) or the proinflammatory cytokines (e.g., interleukin-1 [IL-1] and tumor necrosis factor it induces. To test the possibility that cholecystokinin (CCK) mediates anorexia induced by IL-1 beta and LPS, mice trained to poke their noses in a hole to obtain a food reward according to a fixed ratio (1 reward per 20 actions) were pretreated with the CCK-A receptor antagonist L364,718 (at 1 mg/kg) or with the CCK-B receptor antagonist L365,260 (50 microg/kg) before being injected with LPS (100 microg/kg) or IL-1 beta (20 microg/kg). All injections were given via the intraperitoneal (i.p.) route. In spite of its ability to block the effects of exogenous CCK-8 on food-motivated behavior in mice, the CCK-A receptor antagonist did not block the depressive actions of LPS and IL-1 beta on food-motivated behavior. The CCK-B receptor antagonist was not more effective at blocking. These results do not support a role for CCK in the anorexic effect of LPS and IL-1 beta.

Animals↗
PubMed2000

A new concept in neurodegeneration: TNFalpha is a silencer of survival signals.

The p55 receptor for the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha) is best characterized by its ability to induce signals that trigger cell death. However, this is not the only way in which this TNF receptor kills neurons. A new view of neurodegeneration has recently emerged in which a TNF receptor induces death through the 'silencing of survival signals' (SOSS), such as phosphatidylinositol 3' kinase (PI3 kinase), that are activated by the insulin-like growth factor 1 receptor. This mechanism of intracellular crosstalk is the most pathophysiologically relevant action of TNFalpha in the brain and is applicable to a broad number of receptors that are localized on the same cell. Treatment of the more-devastating and costly neurodegenerative diseases of our time might be best promoted by increasing the efficacy of neuronal survival factors using new approaches aimed at inhibiting the SOSS.

Animals↗
PubMed2000

Early depressive symptoms in cancer patients receiving interleukin 2 and/or interferon alfa-2b therapy.

PURPOSE: Depressive symptomatology is frequently associated with interleukin (IL)-2 and interferon alfa-2b (INFalpha-2b) therapy in cancer patients. The objective of the present study was to evaluate the depressive and anxiety symptoms induced by IL-2 and/or INFalpha-2b in cancer patients during the first days of cytokine immunotherapy. PATIENTS AND METHODS: The study included 48 patients with renal cell carcinoma or melanoma. Patients were treated either with subcutaneous IL-2, alone (n = 20) or in combination with INFalpha-2b (n = 6); or with INFalpha-2b alone, administered subcutaneously at a low dose (n = 8) or intravenously at a high dose (n = 14). Depressive symptoms were evaluated using the Montgomery and Asberg Depression Rating Scale (MADRS), and anxiety symptoms were evaluated using the Covi scale. Evaluations were performed just before initiation of treatment (day 1) and on days 3 and 5 of treatment. RESULTS: Patients treated with IL-2 alone or in association with INFalpha-2b had significantly higher MADRS scores after 5 days of cytokine therapy, and patients who received both cytokines had increased scores on day 3. In contrast, patients treated with INFalpha-2b alone did not have varying MADRS scores during the course of treatment. Cytokine therapy had no effect on anxiety, except in patients treated with IL-2 in combination with INFalpha-2b. In these patients, the enhancement in anxiety scores that was observed on day 5 was mainly attributable to increased somatic complaints. CONCLUSION: IL-2 and INFalpha-2b have differential effects on mood, and IL-2 therapy induces depressive symptoms early in treatment.

Adult↗
PubMed1999

A new mechanism of neurodegeneration: a proinflammatory cytokine inhibits receptor signaling by a survival peptide.

Heightened expression of both a proinflammatory cytokine, tumor necrosis factor alpha (TNF-alpha), and a survival peptide, insulin-like growth factor I (IGF-I), occurs in diverse diseases of the central nervous system, including Alzheimer's disease, multiple sclerosis, the AIDS-dementia complex, and cerebral ischemia. Conventional roles for these two proteins are neuroprotection by IGF-I and neurotoxicity by TNF-alpha. Although the mechanisms of action for IGF-I and TNF-alpha in the central nervous system originally were established as disparate and unrelated, we hypothesized that the signaling pathways of these two cytokines may interact during neurodegeneration. Here we show that concentrations of TNF-alpha as low as 10 pg/ml markedly reduce the capacity of IGF-I to promote survival of primary murine cerebellar granule neurons. TNF-alpha suppresses IGF-I-induced tyrosine phosphorylation of insulin receptor substrate 2 (IRS-2) and inhibits IRS-2-precipitable phosphatidylinositol 3'-kinase activity. These experiments indicate that TNF-alpha promotes IGF-I receptor resistance in neurons and inhibits the ability of the IGF-I receptor to tyrosine-phosphorylate the IRS-2 docking molecule and to subsequently activate the critical downstream enzyme phosphatidylinositol 3'-kinase. This intracellular crosstalk between discrete cytokine receptors reveals a novel pathway that leads to neuronal degeneration whereby a proinflammatory cytokine inhibits receptor signaling by a survival peptide.

Animals↗
PubMed1999

Phosphatidylinositol 3'-kinase, but not S6-kinase, is required for insulin-like growth factor-I and IL-4 to maintain expression of Bcl-2 and promote survival of myeloid progenitors.

Phosphatidylinositol 3'-kinase (PI 3-kinase) catalyzes the formation of 3' phosphoinositides and has been implicated in an intracellular signaling pathway that inhibits apoptosis in both neuronal and hemopoietic cells. Here, we investigated two potential downstream mediators of PI 3-kinase, the serine/threonine p70 S6-kinase (S6-kinase) and the antiapoptotic protein B cell lymphoma-2 (Bcl-2). Stimulation of factor-dependent cell progenitor (FDCP) cells with either IL-4 or insulin-like growth factor (IGF)-I induced a 10-fold increase in the activity of both PI 3-kinase and S6-kinase. Rapamycin blocked 90% of the S6-kinase activity but did not affect PI 3-kinase, whereas wortmannin and LY294002 inhibited the activity of both S6-kinase and PI 3-kinase. However, wortmannin and LY294002, but not rapamycin, blocked the ability of IL-4 and IGF-I to promote cell survival. We next established that IL-3, IL-4, and IGF-I increase expression of Bcl-2 by >3-fold. Pretreatment with inhibitors of PI 3-kinase, but not rapamycin, abrogated expression of Bcl-2 caused by IL-4 and IGF-I, but not by IL-3. None of the cytokines affected expression of the proapoptotic protein Bax, suggesting that all three cytokines were specific for Bcl-2. These data establish that inhibition of PI 3-kinase, but not S6-kinase, blocks the ability of IL-4 and IGF-I to increase expression of Bcl-2 and protect promyeloid cells from apoptosis. The requirement for PI 3-kinase to maintain Bcl-2 expression depends upon the ligand that activates the cell survival pathway.

Animals↗
PubMed1999

Central administration of insulin-like growth factor-1 inhibits lipopolysaccharide-induced sickness behavior in mice.

To assess the possible modulatory effects of insulin-like growth factor-1 (IGF-1) on the brain effects of proinflammatory cytokines, male CD-1 mice were injected into the lateral ventricle of the brain with a behaviorally depressing dose (100 ng) of the cytokine inducer lipopolysaccharide (LPS) and their response to various doses of IGF-1 (0, 100 and 1000 ng) was measured during behavioral tests carried before and at various time intervals after treatment. LPS induced a profound behavioral depression that was abrogated by the higher dose of IGF-1 tested. Since the behavioral effects of LPS are mediated by the local synthesis and results of proinflammatory cytokines, these results indicate that IGF-1 interferes with the production and/or action of proinflammatory cytokines in the brain.

Animals↗
PubMed1999

Expression and localization of p80 and p68 interleukin-1 receptor proteins in the brain of adult mice.

The biological effects of interleukin-1 (IL-1) are mediated by two distinct receptors, the p80 type I IL-1 and p68 type II IL-1 receptor proteins (IL-1RI and IL-1RII, respectively), both of which have been recently co-localized to the growth hormone synthesizing cells of the adenohypophysis. Previous studies have shown that IL-1 can bind to specific structures in the central nervous system, but the distribution of IL-1RI and IL-1RII proteins in the adult mouse brain has not been reported. Here we have used immunohistochemistry to study the expression, distribution and cellular localization of both isoforms of the IL-1 receptor proteins in the adult mouse brain. Using a combination of processing techniques (AMeX fixation and cryosectioning), we have immunolabeled brain sections for each isoform of the IL-1R. Both isoforms are expressed in the CNS, particularly in neuronal soma of the granular layer of the dentate gyrus and pyramidal cells of fields CA1-CA4 of Ammon's horn of the hippocampus, in epithelial cells of the choroid plexus and ependymal layer, and in neuronal soma of Purkinje cells of the cerebellum. The IL-1RII isoform, but not IL-1RI, is expressed in specific neuronal soma and proximal cell processes of neurons of the paraventricular gray matter of the hypothalamus. These immunohistochemical data directly demonstrate the neuronal expression of both IL-1R proteins in situ. The distribution and cellular localization of IL-1R proteins in the CNS provide a molecular basis for understanding reciprocal interactions between the immune system and the brain.

Age Factors↗
PubMed1999

Interleukin-4 and interleukin-10 regulate IL1-beta induced mouse primary astrocyte activation: a comparative study.

The pro-inflammatory cytokine interleukin-1beta (IL-1beta) is strongly expressed during brain injury and is able to induce severe cellular brain damage via the production of soluble factors. Different processes regulate IL-1 biological activities, like the production of anti-inflammatory cytokines such as interleukin-4 (IL-4) and interleukin-10 (IL-10). In this report, we describe the sequential effects of IL-4 and IL-10 on the production of interleukin-6 (IL-6) induced by IL-1beta in mouse primary astrocytes and compare these effects to those of the synthetic glucocorticoid agonist, dexamethasone. IL-6 secretion and IL-6 mRNA expression were determined by ELISA assay and a comparative RT-PCR method, respectively. Incubation of mouse astrocytes in primary culture simultaneously with IL-1beta (10 ng/ml) + IL-10 (10 ng/ml) or IL-1beta + dexamethasone (10(-6) M) markedly reduced IL-1beta induced IL-6 secretion and IL-6 mRNA expression, respectively, whereas simultaneous addition of IL-4 (10 ng/ml) did not alter the induction of IL-6 by IL-1beta. In contrast, after 24 h of IL-1beta treatment, the level of IL-6 was decreased below constitutive levels, and this change was reversed by addition of IL-4. IL-6 production in IL-1beta pretreated cells was also increased by addition of IL-4, whereas IL-10 and dexamethasone had no effects. The delayed time dependent effect of IL-4 might be partially explained by the induction of IL-4 receptor alpha-chain mRNA expression by IL-1beta. Therefore, we conclude that IL-10 and dexamethasone have rapid immunosuppressive effects on the astrocyte response to IL-1beta stimulation, whereas IL-4, which has a delayed action, acts as an immune inducer.

Animals↗
PubMed1999

Increased sensitivity of prediabetic nonobese diabetic mouse to the behavioral effects of IL-1.

The nonobese diabetic (NOD) mouse is a model of spontaneous insulin-dependent diabetes mellitus (IDDM) or type I diabetes. In humans, and in animal models of IDDM, the progression of the disease is modulated by various environmental factors, particularly infectious agents. Interleukin-1 (IL-1) plays a pivotal role in the development of IDDM, and modulation of its synthesis may be a mechanism by which environmental modulation of disease progression occurs. Since various alterations at the level of the gene, number, and sensitivity of IL-1 receptors have been described in different animal models of autoimmune disease, we investigated, in the prediabetic NOD mouse, the presence of IL-1 receptors and their functional behavioral characteristics. Here we present evidence that prediabetic NOD mice exhibit a normal distribution and density of functional brain IL-1 receptors, but are more sensitive to the behavioral effects of IL-1 than the control ICR strain.

Animals↗
PubMed1999

Temporal and spatial relationships between lipopolysaccharide-induced expression of Fos, interleukin-1beta and inducible nitric oxide synthase in rat brain.

Interleukin-1beta plays an important role in mediating central components of the host response to peripheral infection such as fever and neuroendocrine activation by acting in the brain. The present study assessed whether interleukin-1beta produced in the brain is relevant to neuronal activation and the fever response induced by intraperitoneal injection of bacterial lipopolysaccharide. The distributions of Fos protein, interleukin-1beta protein and inducible nitric oxide synthase messenger RNA, used as an anatomical indicator of interleukin-1beta bioactivity, were compared in brains of animals killed 2, 4 or 8 h after lipopolysaccharide (250 microg/kg) or saline injection. Saline did not induce interleukin-1beta or Fos immunoreactivity in the brain. Interleukin-1beta positive cells were found 2 h after lipopolysaccharide injection in circumventricular organs. Fos immunoreactivity at this time-point was not found in circumventricular organs, but in parenchymal structures such as the nucleus of the solitary tract, paraventricular hypothalamus and ventromedial preoptic area. Fos expression did occur in circumventricular organs only 8 h after lipopolysaccharide injection. This late pattern of Fos expression coincided with the rise in body temperature and the induction of inducible nitric oxide synthase messenger RNA. These data show that after peripheral lipopolysaccharide administration interleukin-1beta is synthesized and bioactive in circumventricular organs. Interleukin-1beta may activate local neurons that induce fever and neuroendocrine activation via projections to the ventromedial preoptic area and the nucleus of the solitary tract.

Abdomen↗
PubMed1999

Central injection of IL-10 antagonizes the behavioural effects of lipopolysaccharide in rats.

Peripheral (i.p.) and central (i.c.v.) injections of lipopolysaccharide (LPS) have been shown to induce brain expression of proinflammatory cytokines and to depress social behaviour in rats, increase duration of immobility and induce body weight loss. To determine if the anti-inflammatory cytokine, interleukin-10 (IL-10) is able to modulate these effects, recombinant rat IL-10 was injected in the lateral ventricle of the brain (30, 100, 300 ng/rat) prior to i.p. or i.c.v. injection of LPS (250 micrograms/kg or 60 ng/rat, respectively). Social exploration was depressed for 6 h after i.p. LPS injection. This effect was attenuated by IL-10 (30 and 100 ng) 2 h after injection, whereas the highest dose of IL-10 blocked the depression of social interaction for 6 h after LPS injection. IL-10 produced the same effects on the increase of immobility although the results did not reach significance. Social exploration was depressed 3 h after i.c.v. LPS injection, and this was accompanied by increased immobility. These effects were totally blocked by i.c.v. IL-10 (300 ng/rat). Rats lost body weight after i.c.v. LPS, and this effect was attenuated by i.c.v. IL-10. These results indicate that IL-10 is able to modulate the production and/or action of central proinflammatory cytokines.

Animals↗
PubMed1999

Attentional and mnemonic deficits associated with infectious disease in humans.

BACKGROUND: Infectious diseases are accompanied by behavioural and psychological changes that suggest the implication of the central nervous system. Among them, cognitive alterations have been reported, but their specificity and implication in everyday life are still largely unclear. The purpose of the present study was to evaluate and specify the everyday memory disturbances in sick human subjects and to determinate the role of fever in the appearance of these alterations. METHODS: The study was carried out in a military training centre for naval recruits. Ninety-one volunteer subjects, healthy (N = 30) or suffering from flu-like syndrome, with (N = 29) or without fever (N = 32), participated in this experiment and were administered a cognitive test (the ERBMT) according to a cross-sectional design for assessing various aspects of everyday memory. RESULTS: Sick subjects were specifically impaired in daily memory tasks that require the temporary management of a large amount of information. This impairment was similar for the feverish and apyretic sick subjects who both differed from the controls. CONCLUSION: These findings suggest that infectious disease disturbs the complex cognitive processes that might be associated with attentional functions. Moreover, these results show that fever is not a necessary condition for the appearance of these cognitive disturbances.

Adolescent↗
PubMed1999

Cytokines and depression: fortuitous or causative association?

There is an increasingly impressive database concerning the possible involvement of cytokines in depression and their role in the therapeutic effects of antidepressants. Based on the discussions which took place on these issues at a recent meeting held in Roscoff, France, this perspective summarizes in a critical way the evidence in favor of such a possibility, and points out the needs for further research to clarify both the nature of the subtle dysregulations that affect neuroendocrine-immune interactions in depressive disorders and their contribution to psychopathology.

Antidepressive Agents↗
PubMed1999

Elevated cyclin E levels, inactive retinoblastoma protein, and suppression of the p27(KIP1) inhibitor characterize early development of promyeloid cells into macrophages.

Cyclin-dependent kinase inhibitors such as p27(KIP1) have recently been shown to lead to cellular differentiation by causing cell cycle arrest, but it is unknown whether similar events occur in differentiating promyeloid cells. Hematopoietic progenitor cells undergo lineage-restricted differentiation, which is accompanied by expression of distinct maturation markers. Here we show that the classical growth factor insulin-like growth factor I (IGF-I) potently promotes vitamin D(3)-induced macrophage differentiation of promyeloid cells, as assessed by measurement of a coordinate increase in expression of the integrin alpha subunit CD11b, the CD14 lipopolysaccharide receptor, and the macrophage-specific esterase, alpha-naphthyl acetate esterase, as early as 24 h following initiation of terminal differentiation. Addition of IGF-I to cells undergoing vitamin D(3)-induced differentiation also leads to an early increase in expression of cyclin E, phosphorylation of the retinoblastoma tumor suppressor protein, and a doubling of the cell number. Early expression of CD11b (24 h) is simultaneously accompanied by inhibition in the expression of p27(KIP1). Cell cycle analysis with propidium iodide revealed that CD11b expression at 24 h following initiation of differentiation occurs at all phases of the cell cycle instead of only those cells arrested in G(0)/G(1). Similarly, development of a novel double-labeling intra- and extracellular flow-cytometric technique demonstrated that single cells expressing the mature leukocyte differentiation antigen CD11b can also incorporate the thymidine analog bromodeoxyuridine. Likewise, expression of the intracellular DNA polymerase delta cofactor/proliferating-cell nuclear antigen at 24 h is also simultaneously expressed with the surface marker CD11b, indicating that these cells continue to proliferate early in their differentiation program. Finally, at 24 h following induction of differentiation, IGF-I promoted a fourfold increase in the uptake of [(3)H]thymidine by purified populations of CD11b-expressing cells. Taken together, these data demonstrate that the initial steps associated with terminal macrophage differentiation occur concomitantly with progression through the cell cycle and that these very early differentiation events do not require the accumulation of p27(KIP1).

Cell Cycle↗
PubMed1999

Central administration of rat IL-6 induces HPA activation and fever but not sickness behavior in rats.

Interleukin (IL)-6 has been proposed to mediate several sickness responses, including brain-mediated neuroendocrine, temperature, and behavioral changes. However, the exact mechanisms and sites of action of IL-6 are still poorly understood. In the present study, we describe the effects of central administration of species-homologous recombinant rat IL-6 (rrIL-6) on the induction of hypothalamic-pituitary-adrenal (HPA) activity, fever, social investigatory behavior, and immobility. After intracerebroventricular administration of rrIL-6 (50 or 100 ng/rat), rats demonstrated HPA and febrile responses. In contrast, rrIL-6 alone did not induce changes in social investigatory and locomotor behavior at doses of up to 400 ng/rat. Coadministration of rrIL-6 (100 ng/rat) and rrIL-1beta (40 ng/rat), which alone did not affect the behavioral responses, reduced social investigatory behavior and increased the duration of immobility. Compared with rhIL-6, intracerebroventricular administration of rrIL-6 (100 ng/rat) induced higher HPA responses and early-phase febrile responses. This is consistent with a higher potency of rrIL-6, compared with rhIL-6, in the murine B9 bioassay. We conclude that species-homologous rrIL-6 alone can act in the brain to induce HPA and febrile responses, whereas it only reduces social investigatory behavior and locomotor activity in the presence of IL-1beta.

Adrenocorticotropic Hormone↗