Biomedical subjects

Robert Dantzer

Publications and source records attributed to Robert Dantzer.

At least 19 recordsLinked to original sources

PubMed2006

Twenty years of research on cytokine-induced sickness behavior.

Cytokine-induced sickness behavior was recognized within a few years of the cloning and expression of interferon-alpha, IL-1 and IL-2, which occurred around the time that the first issue of Brain, Behavior, and Immunity was published in 1987. Phase I clinical trials established that injection of recombinant cytokines into cancer patients led to a variety of psychological disturbances. It was subsequently shown that physiological concentrations of proinflammatory cytokines that occur after infection act in the brain to induce common symptoms of sickness, such as loss of appetite, sleepiness, withdrawal from normal social activities, fever, aching joints and fatigue. This syndrome was defined as sickness behavior and is now recognized to be part of a motivational system that reorganizes the organism's priorities to facilitate recovery from the infection. Cytokines convey to the brain that an infection has occurred in the periphery, and this action of cytokines can occur via the traditional endocrine route via the blood or by direct neural transmission via the afferent vagus nerve. The finding that sickness behavior occurs in all mammals and birds indicates that communication between the immune system and brain has been evolutionarily conserved and forms an important physiological adaptive response that favors survival of the organism during infections. The fact that cytokines act in the brain to induce physiological adaptations that promote survival has led to the hypothesis that inappropriate, prolonged activation of the innate immune system may be involved in a number of pathological disturbances in the brain, ranging from Alzheimer's disease to stroke. Conversely, the newly-defined role of cytokines in a wide variety of systemic co-morbid conditions, ranging from chronic heart failure to obesity, may begin to explain changes in the mental state of these subjects. Indeed, the newest findings of cytokine actions in the brain offer some of the first clues about the pathophysiology of certain mental health disorders, including depression. The time is ripe to begin to move these fundamental discoveries in mice to man and some of the pharmacological tools are already available to antagonize the detrimental actions of cytokines.

Adaptation, Physiological↗

PubMed2006

Insulin-like growth factor-I enhances the biological activity of brain-derived neurotrophic factor on cerebrocortical neurons.

Insulin-like growth factor (IGF)-I and brain-derived neurotrophic factor (BDNF) act within the brain to enhance neuronal survival and plasticity. We extend these findings by showing that the presence of both neurotrophins is required to depress the rise in intracellular Ca2+ caused by glutamate in primary cultures of cerebrocortical neurons. IGF-I enhanced expression of BDNF receptors (Trk-B) and increased the ability of BDNF to induce ERK1/2 phosphorylation. This IGF-I-induced increase in BDNF responsiveness describes a new interaction between these peptides in the brain.

Animals↗

PubMed2006

C-jun N-terminal kinase mediates tumor necrosis factor-alpha suppression of differentiation in myoblasts.

The stress kinase c-jun N-terminal kinase (JNK) was recently shown to be involved in the pathophysiology of major inflammatory conditions, including Alzheimer's disease, stroke, obesity, and type II diabetes. However, the role of JNK in regulating inflammatory events in skeletal muscle is only beginning to be explored. IGF-I is the major hormone that promotes muscle growth and development. Here we used a novel, JNK interacting protein (JIP)-derived JNK peptide inhibitor to establish that JNK suppresses the biological activity of IGF-I in skeletal muscle progenitor cells. In these myoblasts, TNFalpha and its downstream receptor substrates, neutral-sphingomyelinase (N-SMase) and N-acetyl-d-sphingosine (C2-ceramide), induce JNK kinase activity in a time-dependent manner. Consistent with these results, TNFalpha induces JNK binding to insulin receptor substrate 1 (IRS-1) but is unable to inhibit IGF-I-induced IRS-1 tyrosine phosphorylation in myoblasts that are treated with the JNK peptide inhibitor. More importantly, JNK activation induced by TNFalpha, C2-ceramide, and N-SMase is associated with reduced expression of the critical muscle transcription factor myogenin as well as the differentiation marker myosin heavy chain (MHC). The JNK peptide inhibitor, but not the control peptide, completely reverses this inhibition of both myogenin and MHC. In the absence of IGF-I, TNFalpha, C2-ceramide, N-SMase and the JNK inhibitor are inactive, as shown by their inability to affect IRS tyrosine phosphorylation and protein expression of myogenin and MHC. These results establish that the resistance of muscle progenitor cells to IGF-I, which is caused by inflammatory stimuli, is mediated by the JNK stress kinase pathway.

Animals↗

PubMed2006

Effects of insulin-like growth factor-I on cytokine-induced sickness behavior in mice.

Central administration of insulin-like growth factor-I (IGF-I) attenuates sickness behavior in response to the cytokine inducer lipopolysaccharide. The present study was designed to determine the respective roles of the two main proinflammatory cytokines, tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta), in these effects. Male CD1 mice were injected into the lateral ventricle (i.c.v.) of the brain with optimal amounts of either TNFalpha (50 ng) or IL-1beta (2 ng) that induce sickness behavior. Behavioral responses to IGF-I (0, .1, and 1 microg) also given i.c.v. were measured at various time intervals before and after treatment with the two proinflammatory cytokines. Mice treated with TNFalpha and IL-1beta lost body weight and displayed equivalent reductions in social exploration and instances of immobility. At the dose of .1 microg, IGF-I attenuated these signs of sickness in TNFalpha-but not in IL-1beta-treated mice. At the dose of 1 microg, IGF-I attenuated IL-1beta-induced immobility and the reduction in social exploration but had no effect on loss of body weight. These findings indicate that IGF-I is more potent in attenuating sickness behavior induced by TNFalpha than that caused by IL-1beta, which is consistent with the relative specificity of the TNFalpha/IGF-I interactions in the brain.

Animals↗

PubMed2006

Cytokine, sickness behavior, and depression.

Sufficient evidence is now available to accept the concept that the brain recognizes cytokines as molecular signals of sickness. Clarifying the way the brain processes information generated by the innate immune system is accompanied by a progressive elucidation of the cellular and molecular components of the intricate system that mediates cytokine-induced sickness behavior. We are still far, however, from understanding the whole. Among the hundreds of genes that proinflammatory cytokines can induce in their cellular targets, only a handful has been examined functionally. In addition, a dynamic view of the cellular interactions that occur at the brain sites of cytokine production and action is missing, together with a clarification of the mechanisms that favor the transition toward pathology.

Animals↗

PubMed2005

Inhibition of vagally mediated immune-to-brain signaling by vanadyl sulfate speeds recovery from sickness.

To the ill patient with diabetes, the behavioral symptoms of sickness such as fatigue and apathy are debilitating and can prevent recuperation. Here we report that peripherally administered insulin-like growth factor 1 (IGF-1) attenuates LPS-dependent depression of social exploration (sickness) in nondiabetic (db/+) but not in diabetic (db/db) mice. We show that the insulin/IGF-1 mimetic vanadyl sulfate (VS) is effective at augmenting recovery from sickness in both db/+ and db/db mice. Specifically, peak illness was reached at 2 h for both VS and control animals injected with LPS, and VS mice recovered 50% faster than non-VS-treated animals. Examination of the mechanism of VS action in db/+ mice showed that VS paradoxically augmented peritoneal macrophage responsivity to LPS, increasing both peritoneal and ex vivo macrophage production of IL-1beta and IL-6 but not TNF-alpha. The effects of VS in promoting recovery from sickness were not restricted to LPS, because they were also observed after direct administration of IL-1beta. To explore the possibility that VS impairs immune-to-brain communication via vagal afferents, the vagally mediated satiety-inducing effects of cholecystokinin 8 were tested in db/+ mice. Cholecystokinin decreased food intake in saline-injected mice but not in VS-treated mice. VS also inhibited LPS-dependent up-regulation of IL-1beta and IL-6 mRNA in the brain, while increasing by 50% the cerebral expression of transcripts of the specific antagonist of IL-1 receptors IL-1RA and IL-1R2. Taken together, these data indicate that VS improves recovery from LPS-induced sickness by blocking vagally mediated immune-to-brain signaling and by up-regulating brain expression of IL-1beta antagonists.

Animals↗

PubMed2005

Pentoxifylline and insulin-like growth factor-I (IGF-I) abrogate kainic acid-induced cognitive impairment in mice.

Hippocampal insults involving neuroimmune mechanisms can impair learning and memory in a variety of tasks. The present study was designed to assess the effect of pentoxifylline, an inhibitor of tumor necrosis factor alpha (TNFalpha), and insulin-like growth factor-I (IGF-I) on kainate (KA)-induced impairment in spatial memory. Male mice received a subcutaneous injection of a dose of KA (15 mg/kg) that had no cytotoxic effect on hippocampal neurons as confirmed by Fluorojade B staining. This dose resulted in an impairment of spatial memory in a two-trial recognition task 11 days later. Intraperitoneal administration of pentoxifylline (200 mg/kg) abrogated this effect. Repeated intracerebroventricular injection of IGF-I (2 microg/mouse on day 1 followed by 1 microg/mouse on days 2-5) abrogated KA-induced deficits in spatial memory whereas acute IGF-I (2 microg/mouse on day 1 only) had mixed effects. These findings indicate that endogenous TNFalpha is probably involved in the detrimental effects of kainate on cognition and that exogenous IGF-I can oppose these effects, probably by antagonizing TNFalpha-induced neurotoxicity.

Analysis of Variance↗

PubMed2005

Cellular distribution of interleukin-1alpha-immunoreactivity after MPTP intoxication in mice.

In young rodents, peripheral injection of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results in a dopaminergic nigrostriatal denervation (during the first week after injection), followed by a spontaneous dopaminergic reinnervation. Sprouting from residual neurons has been proposed to account for this event. It has been shown that an inflammatory process takes place during striatal dopaminergic denervation but its consequences remain controversial. Some clues notably indicate that interleukin (IL)-1alpha may participate in MPTP-induced inflammation and promote recovery. We therefore studied the immunohistochemical localization of IL-1alpha expression in the striatum and ventral mesencephalon at different times (1, 3, 6, 16, and 30 days) after MPTP injection in mice. IL-1alpha-immunoreactivity (ir) was observed in striatum, substantia nigra pars compacta, and ventral tegmental area. Apart from a few localization in mesencephalic activated microglia, IL-1alpha was almost exclusively found in activated astrocytes. However, in the striatal parenchyma, another component of IL-1alpha-ir colocalized with tyrosine hydroxylase (TH)-ir, a marker for dopaminergic neurons. Moreover, some parenchymal TH-positive axons were also found to express the growth cone-associated protein (GAP)-43, a marker for axonal growth cones. In the striatum, IL-1alpha-ir was also detected in a non-astrocytic perivascular component, with a distribution similar to GAP-43-ir. IL-1alpha could thus directly or indirectly influence striatal reorganization after MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2005

Bacille Calmette-Guérin inoculation induces chronic activation of peripheral and brain indoleamine 2,3-dioxygenase in mice.

BACKGROUND: Activation of the indoleamine 2,3-dioxygenase (IDO) enzyme and the resulting decrease in plasma tryptophan (TRP) levels appears to be a crucial link in the relationship between cytokines and depression. We aimed to develop an experimental model of chronic IDO activation based on bacille Calmette-Guérin (BCG) infection that elicits a robust increase in levels of interferon (IFN)- gamma, a key cytokine in the activation of IDO. METHODS: Mice were inoculated intraperitoneally with BCG (10(7) cfu/mouse). Lung and brain IDO activity was measured over time, together with plasma levels of TRP and IFN- gamma. RESULTS: BCG induced, over the course of several weeks, a chronic increase in serum IFN- gamma levels that was associated with a sustained enhancement of lung and brain IDO activity and with decreases in peripheral (serum and lungs) and brain concentrations of TRP, with different time courses between tissues. CONCLUSIONS: The model of BCG-induced IDO activation will be useful for the study of the consequences of peripheral immune activation in the brain and the role of TRP metabolism in cytokine-induced mood alteration.

Animals↗

PubMed2005

A role of IL-1 in MPTP-induced changes in striatal dopaminergic and serotoninergic transporter binding: clues from interleukin-1 type I receptor-deficient mice.

In mice, the MPTP-induced striatal dopaminergic denervation is followed by a spontaneous partial DAT recovery and by serotoninergic hyperinnervation. We show that IL-1RI-deficient mice have a higher DAT decrease in the ventromedial striatum after MPTP and a higher basal serotoninergic innervation of the whole striatum. These data point to a possible role of IL-1RI in the early MPTP-induced structural or functional remodeling of the nigrostriatal dopamine system.

Analysis of Variance↗

PubMed2005

IL-1beta-mediated innate immunity is amplified in the db/db mouse model of type 2 diabetes.

Chronic inflammation appears to play a critical role in type 2 diabetes and its complications. Here we tested the hypothesis that this inflammatory dysregulation affects the IL-1beta system and has functional consequences in the brain. Diabetic, db/db, and nondiabetic, db/+, mice were administered i.p. LPS, a potent cytokine inducer, at a dose of 100 microg/kg/mouse. db/db mouse innate immune-associated sickness behavior was 14.8, 33, 44.7, and 34% greater than that of db/+ mice at 2, 4, 8, and 12 h, respectively. When a fixed dose of LPS was used (5 microg/mouse), db/db mouse sickness was again enhanced 18.4, 22.2, and 14.5% at 4, 8, and 12 h as compared with db/+ mice. In diabetic mice, peritoneal macrophages produced more IL-1beta in response to LPS, and peritoneal levels of IL-1beta induced by LPS were increased. Importantly, IL-1R antagonist and type 2 IL-1 receptor (IL-1R2) failed to up-regulate in response to LPS in db/db mice. Finally, both peripheral and central administration of IL-1beta, itself, induced sickness in db/db mice that mimicked the effects of peripheral LPS and was significantly greater than that seen in db/+ mice. Taken together, these results indicate that IL-1beta-mediated innate immunity is augmented in db/db mice both at the periphery and in the brain, and the mechanism is due to diabetes-associated loss of IL-1beta counterregulation.

Animals↗

PubMed2005

The taste of sickness: lipopolysaccharide-induced finickiness in rats.

Decrease in food intake is one of the most documented non-specific symptoms of inflammatory processes. However, attention has been mainly focused on quantitative analysis. The present paper reports studies undertaken to test the possible contribution of changes in taste processes in inflammatory-induced alteration of feeding behavior. In a first experiment, the effects of lipopolysaccharide-induced sickness were assessed on preference for saccharin and aversion for quinine in rats using the two-bottle test paradigm. In a second experiment, effect of lipopolysaccharide (LPS) on the behavioral reactivity to palatable, unpalatable and mixed solutions was analyzed using the taste-reactivity paradigm. Our results show that LPS decreased total fluid intake but did not change taste responses to unpalatable or palatable substances. However, LPS increased aversive reactions and decreased hedonic responses to mixed taste. These LPS-induced changes are interpreted as an increase in finickiness and are discussed in regard to their potential role in the adaptation of individuals to sickness.

Animals↗

PubMed2005

Somatization: a psychoneuroimmune perspective.

The concept of somatization has a long history in psychosomatic medicine. What is missing, however, is an understanding of the way patients are able to perceive and represent somatic symptoms. Recent advances in psychoneuroimmunology offer new perspectives in this area. Proinflammatory cytokines produced by cells of the innate immune system in response to pathogen-associated molecular patterns and to endogenous danger signals act on the central nervous system via afferent and humoral pathways to trigger a brain cytokine system that organizes the sickness response in its subjective, behavioral, and metabolic components. There is evidence that prolonged activation of this system can precipitate the development of depressive disorders in vulnerable patients. The mechanisms that are responsible for the transition from sickness to depression involve alterations in tryptophan metabolism. There is also some indication that the brain cytokine system can become sensitized in response to non-immune stressors or to immune stressors occurring early in life. All these new findings have the potential to contribute to a renewed biopsychological approach to somatization and somatoform disorders.

Animals↗

PubMed2005

NFkappaB activates in vivo the synthesis of inducible Cox-2 in the brain.

Interleukin-1beta (IL-1beta) induces cyclooxygenase-2 (Cox-2) expression in many of its cellular targets resulting in production and release of prostaglandins. Although IL-1beta-induced Cox-2 expression most likely requires activation of nuclear transcription factor kappa B (NFkappaB) pathway, this has never been formally demonstrated in vivo. We tested this using a specific inhibitor of NFkappaB activation, the NEMO binding domain (NBD) peptide, that has been shown previously to be effective in various in vivo models of acute inflammation. Incubation of rat glioma cells with the NBD peptide blocked IL-1beta-induced NFkappaB nuclear translocation. Furthermore, after injection of a biotinylated version of the NBD peptide into the lateral ventricle of the brain, we found that it readily diffused to its potential cellular targets in vivo. To test the effects of the peptide on NFkappaB activation and Cox-2 expression in the brain, we injected it intracerebroventricularly (36 microg/rat) into rats before intraperitoneal injection of IL-1beta (60 microg/kg). Treatment with NBD peptide completely abolished IL-1beta-induced NFkappaB activation and Cox-2 synthesis in microvasculature. In contrast, the peptide had no effect on constitutive neuronal Cox-2. These findings strongly support the hypothesis that IL-1beta-induced NFkappaB activation plays a major role in transmission of immune signals from the periphery to the brain.

Animals↗

PubMed2005

Inactivation of the cerebral NFkappaB pathway inhibits interleukin-1beta-induced sickness behavior and c-Fos expression in various brain nuclei.

The behavioral effects of peripherally administered interleukin-1beta (IL-1beta) are mediated by the production of cytokines and other proinflammatory mediators at the level of the blood-brain interface and by activation of neural pathway. To assess whether this action is mediated by NFkappaB activation, rats were injected into the lateral ventricle of the brain with a specific inhibitor of NFkappaB activation, the NEMO Binding Domain (NBD) peptide that has been shown previously to abolish completely IL-1beta-induced NFkappaB activation and Cox-2 synthesis in the brain microvasculature. NFkappaB pathway inactivation significantly blocked the behavioral effects of intraperitoneally administered IL-1beta in the form of social withdrawal and decreased food intake, and dramatically reduced IL-1beta-induced c-Fos expression in various brain regions as paraventricular nucleus, supraoptic nucleus, and lateral part of the central amygdala. These findings strongly support the hypothesis that IL-1beta-induced NFkappaB activation at the blood-brain interface is a crucial step in the transmission of immune signals from the periphery to the brain that underlies further events responsible of sickness behavior.

Analysis of Variance↗

PubMed2005

Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms.

BACKGROUND: Psychiatric side effects are common during interferon-alfa (IFN-alfa) therapy and often responsible for early treatment discontinuation, thus limiting its therapeutic potential. Depression is considered the hallmark of these side effects. However, irritability, anger/hostility, and manic/hypomanic episodes have also been reported, suggesting that these symptoms are important features of IFN-alfa-induced neuropsychiatric side effects. OBJECTIVE: The aim of this prospective study was to use item-by-item analysis to thoroughly characterize neuropsychiatric symptoms occurring during early IFN-alfa therapy in a large cohort of patients with chronic hepatitis C. METHOD: Ninety-three previously IFN-alfa-naive patients treated with pegylated IFN-alfa plus ribavirin for chronic hepatitis C were studied. Neuropsychiatric assessments were conducted before initiation and after weeks 4 and 12 of antiviral therapy. They included the Mini-International Neuropsychiatric Interview, the 10-item Montgomery-Asberg Depression Rating Scale, the State-Trait Anxiety Inventory, and the Brief Fatigue Inventory. RESULTS: Psychiatric events occurred in 30 patients (32%). They consisted of mood disorders in all cases: mania in 3 cases (10%), irritable hypomania in 15 cases (50%), and depressive mixed states in 12 cases (40%). Neurovegetative symptoms appeared within 4 weeks in most patients. In patients who developed mood disorders, sadness and depressive thoughts were present but minimal in severity. In contrast, inner tension and anxiety symptoms increased significantly over time only in these patients. CONCLUSIONS: Our results suggest that IFN-alfa-induced mood disorders are common and consist of an overlap between depressive and manic symptoms rather than a mere depression. The impact of such findings on therapeutic management should be investigated.

Bipolar Disorder↗

PubMed2004

Social factors and individual vulnerability to chronic stress exposure.

The stress-response is adaptive in the short-term, but it can be maladaptive if sustained levels of its mediators are chronically maintained. Furthermore, not all individuals exposed to chronic stress will progress to disease. Thus, understanding the causes of individual differences and the consequences of variation in vulnerability is of major importance. The aim of this review is to shed light on this issue by presenting a new naturalistic model of chronic psychosocial stress in male mice. Resident/intruder pairs of mice lived in continuous sensory contact and physically interacted daily. Four categories were identified: Resident Dominant, Resident Subordinate (RS), Intruder Dominant, and Intruder Subordinate. Behavior, autonomic and immune functions, hypothalamic-pituitary-adrenocortical responses, brain cytokine expression and cardiac histology were investigated in stress-exposed mice. Certain stress-induced alterations were present in all mice independent of their social status, while others clearly differentiated dominants from subordinates. RS mice showed a unique profile of alterations suggesting that the loss of relevant resources, such as the territory, is the key factor determining why only certain stress-exposed individuals ultimately show malignancy and psychopathologies.

Aggression↗

PubMed2004

Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity.

Sickness refers to a coordinated set of subjective, behavioural and physiological changes that develop in sick individuals during the course of an infection. These changes are due to the effects of interleukin-1 (IL-1) and other proinflammatory cytokines on brain cellular targets. Sickness behaviour is mediated by proinflammatory cytokines that are temporarily expressed in the brain during infection. These centrally produced cytokines are the same as those expressed by innate immune cells and they act on brain receptors that are identical to those characterized on immune cells. Primary afferent nerves represent the main communication pathway between peripheral and central cytokines. Proinflammatory cytokines modulate learning and memory processes. The expression and action of proinflammatory cytokines in the brain in response to peripheral cytokines are regulated by various molecular intermediates including anti-inflammatory cytokines such as interleukin-10 (IL-10) and the IL-1 receptor antagonist (IL-1ra), growth factors such as insulin-like growth factor-1 (IGF-1), hormones such as glucocorticoids and neuropeptides such as vasopressin and alpha-melanotropin.

Animals↗