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1.
Mol Psychiatry ; 23(2): 335-343, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-27752078

RESUMEN

Inflammatory cytokines are commonly elevated in acute depression and are associated with resistance to monoaminergic treatment. To examine the potential role of cytokines in the pathogenesis and treatment of depression, we carried out a systematic review and meta-analysis of antidepressant activity of anti-cytokine treatment using clinical trials of chronic inflammatory conditions where depressive symptoms were measured as a secondary outcome. Systematic search of the PubMed, EMBASE, PsycINFO and Cochrane databases, search of reference lists and conference abstracts, followed by study selection process yielded 20 clinical trials. Random effect meta-analysis of seven randomised controlled trials (RCTs) involving 2370 participants showed a significant antidepressant effect of anti-cytokine treatment compared with placebo (standardised mean difference (SMD)=0.40, 95% confidence interval (CI), 0.22-0.59). Anti-tumour necrosis factor drugs were most commonly studied (five RCTs); SMD=0.33 (95% CI; 0.06-0.60). Separate meta-analyses of two RCTs of adjunctive treatment with anti-cytokine therapy and eight non-randomised and/or non-placebo studies yielded similar small-to-medium effect estimates favouring anti-cytokine therapy; SMD=0.19 (95% CI, 0.00-0.37) and 0.51 (95% CI, 0.34-0.67), respectively. Adalimumab, etanercept, infliximab and tocilizumab all showed statistically significant improvements in depressive symptoms. Meta-regression exploring predictors of response found that the antidepressant effect was associated with baseline symptom severity (P=0.018) but not with improvement in primary physical illness, sex, age or study duration. The findings indicate a potentially causal role for cytokines in depression and that cytokine modulators may be novel drugs for depression in chronically inflamed subjects. The field now requires RCTs of cytokine modulators using depression as the primary outcome in subjects with high inflammation who are free of other physical illnesses.


Asunto(s)
Citocinas/metabolismo , Citocinas/fisiología , Depresión/tratamiento farmacológico , Antidepresivos/uso terapéutico , Enfermedad Crónica , Citocinas/antagonistas & inhibidores , Depresión/metabolismo , Trastorno Depresivo/tratamiento farmacológico , Humanos , Inflamación/tratamiento farmacológico
2.
Transl Psychiatry ; 7(5): e1115, 2017 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-28463241

RESUMEN

A subgroup of individuals with mood and psychotic disorders shows evidence of inflammation that leads to activation of the kynurenine pathway and the increased production of neuroactive kynurenine metabolites. Depression is hypothesized to be causally associated with an imbalance in the kynurenine pathway, with an increased metabolism down the 3-hydroxykynurenine (3HK) branch of the pathway leading to increased levels of the neurotoxic metabolite, quinolinic acid (QA), which is a putative N-methyl-d-aspartate (NMDA) receptor agonist. In contrast, schizophrenia and psychosis are hypothesized to arise from increased metabolism of the NMDA receptor antagonist, kynurenic acid (KynA), leading to hypofunction of GABAergic interneurons, the disinhibition of pyramidal neurons and striatal hyperdopaminergia. Here we present results that challenge the model of excess KynA production in affective psychosis. After rigorous control of potential confounders and multiple testing we find significant reductions in serum KynA and/or KynA/QA in acutely ill inpatients with major depressive disorder (N=35), bipolar disorder (N=53) and schizoaffective disorder (N=40) versus healthy controls (N=92). No significant difference was found between acutely ill inpatients with schizophrenia (n=21) and healthy controls. Further, a post hoc comparison of patients divided into the categories of non-psychotic affective disorder, affective psychosis and psychotic disorder (non-affective) showed that the greatest decrease in KynA was in the affective psychosis group relative to the other diagnostic groups. Our results are consistent with reports of elevations in proinflammatory cytokines in psychosis, and preclinical work showing that inflammation upregulates the enzyme, kynurenine mono-oxygenase (KMO), which converts kynurenine into 3-hydroxykynurenine and quinolinic acid.


Asunto(s)
Trastornos Psicóticos Afectivos/metabolismo , Ácido Quinurénico/sangre , Quinurenina 3-Monooxigenasa/metabolismo , Adulto , Trastornos Psicóticos Afectivos/sangre , Trastornos Psicóticos Afectivos/fisiopatología , Trastorno Bipolar/metabolismo , Cuerpo Estriado/metabolismo , Citocinas/metabolismo , Depresión/metabolismo , Trastorno Depresivo Mayor/metabolismo , Femenino , Neuronas GABAérgicas/metabolismo , Humanos , Inflamación/enzimología , Ácido Quinurénico/metabolismo , Quinurenina/análogos & derivados , Quinurenina/metabolismo , Masculino , Persona de Mediana Edad , Trastornos Psicóticos/metabolismo , Ácido Quinolínico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/metabolismo
3.
Psychol Med ; 47(13): 2229-2237, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28418288

RESUMEN

Accumulating evidence indicate a role for the immune system particularly inflammation and autoimmunity in the aetiology of major psychiatric disorders such as depression and schizophrenia. In this paper, we discuss some of the key advances in immunopsychiatry in order to highlight to psychiatrists and other health professionals how an increased understanding of this field might enhance our knowledge of illness mechanism and approaches to treatment. We present a brief overview of clinical research that link inflammation and autoimmunity with depression and psychosis, including potential role of inflammation in treatment response, current evidence for the effectiveness of immune-modulating treatment for depression and psychosis, and possible role of inflammation in common physical comorbidities for these disorders such as coronary heart disease and diabetes mellitus. Gaining a better understanding of the role of immune system could be paradigm changing for psychiatry. We need collaborations between clinicians and scientists to deliver high-quality translational research in order to fully realise the clinical potential of this exciting and rapidly expanding field.


Asunto(s)
Autoinmunidad/inmunología , Trastorno Depresivo/inmunología , Inmunoterapia/métodos , Inflamación/complicaciones , Esquizofrenia/inmunología , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/etiología , Humanos , Inflamación/tratamiento farmacológico , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/etiología
4.
Pharmacol Rev ; 66(1): 80-101, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24335193

RESUMEN

Comorbid depression and chronic pain are highly prevalent in individuals suffering from physical illness. Here, we critically examine the possibility that inflammation is the common mediator of this comorbidity, and we explore the implications of this hypothesis. Inflammation signals the brain to induce sickness responses that include increased pain and negative affect. This is a typical and adaptive response to acute inflammation. However, chronic inflammation induces a transition from these typical sickness behaviors into depression and chronic pain. Several mechanisms can account for the high comorbidity of pain and depression that stem from the precipitating inflammation in physically ill patients. These mechanisms include direct effects of cytokines on the neuronal environment or indirect effects via downregulation of G protein-coupled receptor kinase 2, activation of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase that generates neurotropic kynurenine metabolites, increased brain extracellular glutamate, and the switch of GABAergic neurotransmission from inhibition to excitation. Despite the existence of many neuroimmune candidate mechanisms for the co-occurrence of depression and chronic pain, little work has been devoted so far to critically assess their mediating role in these comorbid symptoms. Understanding neuroimmune mechanisms that underlie depression and pain comorbidity may yield effective pharmaceutical targets that can treat both conditions simultaneously beyond traditional antidepressants and analgesics.


Asunto(s)
Depresión/epidemiología , Dolor/epidemiología , Animales , Encéfalo , Comorbilidad , Depresión/inmunología , Humanos , Inflamación/epidemiología , Inflamación/inmunología , Dolor/inmunología
5.
Mol Psychiatry ; 15(4): 393-403, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19918244

RESUMEN

Cytokine-induced activation of indoleamine 2,3-dioxygenase (IDO) catabolizes L-tryptophan (TRP) into L-kynurenine (KYN), which is metabolized to quinolinic acid (QUIN) and kynurenic acid (KA). QUIN and KA are neuroactive and may contribute to the behavioral changes experienced by some patients during exposure to inflammatory stimuli such as interferon (IFN)-alpha. A relationship between depressive symptoms and peripheral blood TRP, KYN and KA during treatment with IFN-alpha has been described. However, whether peripheral blood changes in these IDO catabolites are manifest in the brain and whether they are related to central nervous system cytokine responses and/or behavior is unknown. Accordingly, TRP, KYN, QUIN and KA were measured in cerebrospinal fluid (CSF) and blood along with CSF concentrations of relevant cytokines, chemokines and soluble cytokine receptors in 27 patients with hepatitis C after approximately 12 weeks of either treatment with IFN-alpha (n=16) or no treatment (n=11). Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale. IFN-alpha significantly increased peripheral blood KYN, which was accompanied by marked increases in CSF KYN. Increased CSF KYN was in turn associated with significant increases in CSF QUIN and KA. Despite significant decreases in peripheral blood TRP, IFN-alpha had no effect on CSF TRP concentrations. Increases in CSF KYN and QUIN were correlated with increased CSF IFN-alpha, soluble tumor necrosis factor-alpha receptor 2 and monocyte chemoattractant protein-1 as well as increased depressive symptoms. In conclusion, peripheral administration of IFN-alpha activated IDO in concert with central cytokine responses, resulting in increased brain KYN and QUIN, which correlated with depressive symptoms.


Asunto(s)
Depresión/etiología , Hepatitis C , Interferón-alfa/uso terapéutico , Quinurenina/líquido cefalorraquídeo , Triptófano/líquido cefalorraquídeo , Adulto , Antivirales/uso terapéutico , Quimiocina CCL2/líquido cefalorraquídeo , Cromatografía Líquida de Alta Presión/métodos , Citocinas/líquido cefalorraquídeo , Depresión/líquido cefalorraquídeo , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Hepatitis C/sangre , Hepatitis C/líquido cefalorraquídeo , Hepatitis C/complicaciones , Hepatitis C/inmunología , Humanos , Quinurenina/sangre , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Ácido Quinolínico/sangre , Ácido Quinolínico/líquido cefalorraquídeo , Receptores Tipo II del Factor de Necrosis Tumoral/líquido cefalorraquídeo , Ribavirina/uso terapéutico , Estadística como Asunto , Triptófano/sangre
6.
Mol Psychiatry ; 14(5): 511-22, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-18195714

RESUMEN

Although elevated activity of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) has been proposed to mediate comorbid depression in inflammatory disorders, its causative role has never been tested. We report that peripheral administration of lipopolysaccharide (LPS) activates IDO and culminates in a distinct depressive-like behavioral syndrome, measured by increased duration of immobility in both the forced-swim and tail suspension tests. Blockade of IDO activation either indirectly with the anti-inflammatory tetracycline derivative minocycline, that attenuates LPS-induced expression of proinflammatory cytokines, or directly with the IDO antagonist 1-methyltryptophan (1-MT), prevents development of depressive-like behavior. Both minocycline and 1-MT normalize the kynurenine/tryptophan ratio in the plasma and brain of LPS-treated mice without changing the LPS-induced increase in turnover of brain serotonin. Administration of L-kynurenine, a metabolite of tryptophan that is generated by IDO, to naive mice dose dependently induces depressive-like behavior. These results implicate IDO as a critical molecular mediator of inflammation-induced depressive-like behavior, probably through the catabolism of tryptophan along the kynurenine pathway.


Asunto(s)
Depresión/inducido químicamente , Regulación de la Expresión Génica/efectos de los fármacos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Lipopolisacáridos/farmacología , Animales , Conducta Animal/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Citocininas/metabolismo , Depresión/sangre , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Suspensión Trasera/métodos , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Quinurenina/efectos adversos , Quinurenina/sangre , Masculino , Ratones , Ratones Endogámicos ICR , Minociclina/farmacología , Minociclina/uso terapéutico , Actividad Motora/efectos de los fármacos , Natación , Factores de Tiempo , Triptófano/análogos & derivados , Triptófano/sangre , Triptófano/farmacología , Triptófano/uso terapéutico
7.
Eur J Neurosci ; 28(12): 2499-510, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19087175

RESUMEN

Although receptors for the pro-inflammatory cytokine interleukin-1 have long been known to be expressed in the brain, their role in fever and behavioural depression observed during the acute phase response (APR) to tissue infection remains unclear. This may in part be due to the fact that interleukin-1 in the brain is bioactive only several hours after peripheral administration of bacterial lipopolysaccharide (LPS). To study the role of cerebral interleukin-1 action in temperature and behavioural changes, and activation of brain structures during the APR, interleukin-1 receptor antagonist (IL-1ra; 100 microg) was infused into the lateral brain ventricle 4 h after intraperitoneal (i.p.) LPS injection (250 microg/kg) in rats. I.p. LPS administration induced interleukin-1beta (IL-1beta) production in systemic circulation as well as in brain circumventricular organs and the choroid plexus. Intracerebroventricular (i.c.v.) infusion of IL-1ra 4 h after i.p. LPS injection attenuated the reduction in social interaction, a cardinal sign of behavioural depression during sickness, and c-Fos expression in the amygdala and bed nucleus of the stria terminalis. However, LPS-induced fever, rises in plasma corticosterone, body weight loss and c-Fos expression in the hypothalamus and caudal brainstem were not altered by i.c.v. infusion of IL-1ra. These findings, together with our previous observations showing that i.c.v. infused IL-1ra diffuses throughout perivascular spaces, where macrophages express interleukin-1 receptors, can be interpreted to suggest that circulating or locally produced brain IL-1beta acts on these cells to bring about behavioural depression and activation of limbic structures during the APR after peripheral LPS administration.


Asunto(s)
Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Depresión/metabolismo , Interleucina-1/metabolismo , Lipopolisacáridos/farmacología , Animales , Conducta Animal/fisiología , Temperatura Corporal , Peso Corporal , Encéfalo/anatomía & histología , Corticosterona/sangre , Fiebre/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/genética , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Interleucina-1beta/metabolismo , Masculino , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Wistar , Conducta Social
8.
Psychopharmacology (Berl) ; 197(4): 629-35, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18274729

RESUMEN

RATIONALE: Tumor necrosis factor-alpha (TNFalpha) acts within the brain to induce sickness behavior, but the molecular mechanisms are still unknown. TNFalpha binding induces receptor trimerization, activation of c-Jun N-terminal kinase (JNK), and induction of downstream transcription factors. OBJECTIVES: We hypothesized that TNFalpha-induced sickness behavior can be blocked by a novel JNK inhibitor. METHODS: To test this idea, we used a bipartite protein consisting of a ten-amino-acid sequence of the trans-activating domain of the viral TAT protein (D-TAT) linked to a 19-amino-acid peptide that specifically inhibits JNK activation (D-JNKI-1). C57BL/6J mice were pre-treated intracerebroventricularly (i.c.v.) with D-JNKI-1 or the control peptide containing only the protein transduction domain, D-TAT. Mice were then injected centrally with an optimal amount of TNFalpha (50 ng/mouse) to induce sickness behavior. Sickness was assessed as a decrease in social exploration of a novel juvenile, an increase in duration of immobility and loss of body weight. RESULTS: Pre-treatment with D-JNKI-1 (10 ng/mouse), but not D-TAT, significantly inhibited all three indices of sickness induced by central TNFalpha. CONCLUSIONS: These findings demonstrate that D-JNKI-1 can abrogate TNFalpha-induced sickness behavior and suggest a potential therapeutic target for treating major depressive disorders that develop on a background of cytokine-induced sickness behavior.


Asunto(s)
Apetito/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Actividad Motora/efectos de los fármacos , Péptidos/farmacología , Factor de Necrosis Tumoral alfa/toxicidad , Animales , Encéfalo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Conducta Exploratoria , Inyecciones Intraventriculares , Masculino , Ratones , Premedicación , Transducción de Señal/efectos de los fármacos
9.
Neurobiol Aging ; 29(4): 614-21, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17174449

RESUMEN

The number of older adults with HIV-1 disease is increasing but little is known about how age influences behavioral deficits associated with HIV-1 infection. The purpose of this study was to determine in a murine model if aging influenced sickness behavior following central injection of HIV-1 gp120. In initial studies, behavioral deficits induced by acute and repeated intracerebroventricular (ICV) injection of gp120 were greater in aged mice than in adults. Furthermore, repeated ICV injection of gp120 increased hippocampal levels of IL-1 beta and IL-6 mRNA in aged mice but not in adults. To determine if IL-6, which is elevated in aged brain, affects expression of the gp120-binding target, CCR5, microglia (BV-2 cell line) were incubated with increasing concentrations of IL-6. Cell surface expression of CCR5 was increased by IL-6 in a dose-dependent manner. Additionally, IL-6 increased gp120-dependent chemotaxis. These results suggest that aging increases the sensitivity of mice to behavioral deficits caused by ICV gp120, perhaps by increasing expression of CCR5 and augmenting production of cytokines.


Asunto(s)
Envejecimiento/metabolismo , Encéfalo/metabolismo , Encéfalo/virología , Proteína gp120 de Envoltorio del VIH/administración & dosificación , Conducta Social , Envejecimiento/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Línea Celular , Células Cultivadas , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos BALB C , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología
10.
Neurobiol Aging ; 29(11): 1744-53, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17543422

RESUMEN

Age-associated changes in glial reactivity may predispose individuals to exacerbated neuroinflammatory cytokine responses that are permissive to cognitive and behavioral complications. The purpose of this study was to determine if aging is associated with an exaggerated sickness response to central innate immune activation. Our results show that intracerebroventricular (i.c.v.) administration of lipopolysaccharide (LPS) caused a heightened proinflammatory cytokine response (IL-1beta, IL-6, and TNFalpha) in the cerebellum 2h post i.c.v. injection in aged mice compared to adults. This amplified inflammatory profile was consistent with a brain region-dependent increase in reactive glial markers (MHC class II, TLR2 and TLR4). Moreover, LPS caused a prolonged sickness behavior response in aged mice that was paralleled by a protracted expression of brain cytokines in the cerebellum and hippocampus. Finally, central LPS injection caused amplified and prolonged IL-6 levels at the periphery of aged mice. Collectively, these data establish that activation of the central innate immune system leads to exacerbated neuroinflammation and prolonged sickness behavior in aged as compared to adult mice.


Asunto(s)
Envejecimiento/inmunología , Encéfalo/fisiopatología , Citocinas/inmunología , Encefalitis/inducido químicamente , Encefalitis/inmunología , Regulación de la Expresión Génica/inmunología , Lipopolisacáridos , Envejecimiento/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Ventrículos Cerebrales/efectos de los fármacos , Ventrículos Cerebrales/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C
11.
J Neuroendocrinol ; 18(6): 426-33, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16684132

RESUMEN

Cocaine- and amphetamine-regulated transcript (CART) mRNA and peptides are abundant in the adenohypophysis, but their role in pituitary function has not yet been elucidated. CART peptides were recently shown to colocalise with luteinising hormone (LH) or prolactin in rat anterior pituitary, and contradictory results concerning the peptide effects on pituitary hormonal secretions were obtained in vitro from pituitary cell cultures. Thus, we reinvestigated the expression of CART mRNA within the pituitary. Immunohistochemistry for pituitary hormones was performed on sections from adult male Wistar rats followed by in situ hybridisation using CART mRNA antisense 35S-labelled probes. The most represented CART-expressing cells were lactotrophs (42 +/- 1% of CART cells) and gonadotrophs (32 +/- 3%), followed by thyrotrophs (10 +/- 2%), corticotrophs (7 +/- 2%) and somatotrophs (6 +/- 1%). In the pars tuberalis, CART mRNA was easily detectable in gonadotrophs and lactotrophs and, to a lesser extent, in corticotrophs and thyrotrophs. CART peptide was quickly and potently released from perifused pituitary by depolarisation (K+ 30 mM for 15 min; 465 +/- 37% over basal release, n = 5). Gonadotrophin-releasing hormone and thyrotrophin-releasing hormone (0.1 microM) were also active to a lesser extent (138 +/- 11% and 71 +/- 17, n = 7, respectively). CART (0.1 microM) did not modify basal LH or prolactin release but selectively inhibited K+-induced LH release without affecting K+-induced prolactin secretion. Pituitary CART mRNA and content were sex dependent and varied during the oestrous cycle, being lower in dioestrous 2. Pituitary CART content also varied widely amongst rat strains being five to six-fold higher in Wistar and Fischer rats compared to Brown Norway and Lou C rats. Ageing differentially affected pituitary CART mRNA and content, resulting in a marked decrease in Lou C and an increase in Wistar and Sprague-Dawley rats. Taken together, these results suggest that pituitary CART expression is dependent of the sex steroid environment and may be physiologically involved in LH secretion.


Asunto(s)
Ciclo Estral/fisiología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Adenohipófisis/fisiología , Envejecimiento/fisiología , Animales , Ingestión de Alimentos/fisiología , Retroalimentación Fisiológica/fisiología , Femenino , Regulación de la Expresión Génica/fisiología , Hipotálamo/fisiología , Hormona Luteinizante/metabolismo , Masculino , Obesidad/genética , Obesidad/fisiopatología , Fenotipo , ARN Mensajero/análisis , Ratas , Ratas Endogámicas BN , Ratas Endogámicas F344 , Ratas Wistar , Factores Sexuales , Especificidad de la Especie
12.
Neuroscience ; 134(3): 921-32, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16039791

RESUMEN

Interleukin-1beta is released at the periphery during infection and acts on the nervous system to induce fever, neuroendocrine activation, and behavioral changes. These effects are mediated by brain type I IL-1 receptors. In vitro studies have shown the ability of interleukin-1beta to activate mitogen-activated protein kinase signaling pathways including p38, c-Jun N-terminal kinase and extracellular signal-regulated protein kinase 1 and 2 (ERK1/2). In contrast to other mitogen-activated protein kinases, little is known about ERK1/2 activation in the rat brain in response to interleukin-1beta. The aim of the present study was therefore to investigate spatial and temporal activation of ERK1/2 in the rat brain after peripheral administration of interleukin-1beta using immunohistochemistry to detect the phosphorylated form of the kinase. In non-stimulated conditions, phosphorylated ERK1/2 immunoreactivity was observed in neurons throughout the brain. Administration of interleukin-1beta (60 microg/kg, i.p.) induced the phosphorylation of ERK1/2 in areas at the interface between brain and blood or cerebrospinal fluid: meninges, circumventricular organs, endothelial like cells of the blood vessels, and in brain nuclei involved in behavioral depression, fever and neuroendocrine activation: paraventricular nucleus of the hypothalamus, supraoptic nucleus, central amygdala and arcuate nucleus. Double labeling of phosphorylated ERK1/2 and cell markers revealed the expression of phosphorylated ERK1/2 in neurons, astrocytes and microglia. Since phosphorylated ERK1/2 was found in structures in which type I IL-1 receptor has already been identified as well as in structures lacking this receptor, activation of ERK1/2 is likely to occur in response to both direct and indirect action of interleukin-1beta on its target cells.


Asunto(s)
Encéfalo/efectos de los fármacos , Interleucina-1/administración & dosificación , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Encéfalo/citología , Encéfalo/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica/métodos , Interleucina-1/metabolismo , Lectinas/metabolismo , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fosfopiruvato Hidratasa/metabolismo , Fosforilación , Ratas , Ratas Wistar , Factores de Tiempo
13.
Brain Behav Immun ; 16(5): 596-601, 2002 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-12401474

RESUMEN

The essential amino-acid, L-tryptophan, is the precursor of serotonin. Its availability in the brain is controlled by indoleamine 2,3-dioxygenase (IDO). This enzyme is inducible by cytokines such as interferon-gamma (IFN-gamma) and is the first and rate-limiting enzyme of the catabolism pathway of tryptophan. Since induction of IDO has been proposed to mediate the influence of cytokines on mood in patients with various somatic disorders, the present study aimed at analyzing the relationships between changes in brain IDO activity and serum IFN-gamma levels in response to peripheral immune stimulation by lipopolysaccharide (LPS) and superantigen in mice. Each of these treatments induced an increase in serum IFN-gamma at 6 h post-treatment followed 24 h later by a two-fold increase in IDO activity in the brain. These results support the involvement of peripheral IFN-gamma in the control of L-tryptophan catabolism in the brain.


Asunto(s)
Encéfalo/enzimología , Interferón gamma/sangre , Lipopolisacáridos/metabolismo , Superantígenos/metabolismo , Triptófano Oxigenasa/metabolismo , Triptófano/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa , Interferón gamma/efectos de los fármacos , Interferón gamma/metabolismo , Lipopolisacáridos/administración & dosificación , Masculino , Ratones , Ratones Endogámicos BALB C , Superantígenos/administración & dosificación , Triptófano Oxigenasa/efectos de los fármacos
14.
Stress ; 5(2): 131-5, 2002 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12186691

RESUMEN

A previous exposure to an inflammatory reaction is known to increase or decrease the activation of the hypothalamic-pituitary-adrenal (HPA) axis induced by a psychological/physical stress. Beside HPA activation, the non- specific responses to these two kinds of stresses involve the immune system including the production of cytokines. Therefore, they could interfere in cytokine production. In order to test this hypothesis, female C3H mice were first injected i.p. with 5 microg of lipopolysaccharide (LPS) or not (C). Eight days later, half of them were submitted to a 4 h-restraint (R) applied during the nocturnal part of the dark-light cycle and sacrificed immediately after (groups LPS-R and C-R), while the non restrained mice stayed in their home cages (groups LPS-C and C-C). Restraint induced an increase in corticosterone production that was not altered by the previous administration of LPS. It had no effect on mitogen-induced lymphoproliferation. However, restraint induced an augmentation of plasma concentrations of interleukin (IL)-1 and IL-6 that was not observed in animals previously exposed to LPS. These results show that restraint, which represents a psychological stress is able to induce the production of plasma cytokines in mice. They also suggest that LPS may induce a long lasting suppression of plasma cytokines through mechanisms that remain to be elucidated.


Asunto(s)
Citocinas/sangre , Lipopolisacáridos/farmacología , Restricción Física , Estrés Psicológico/sangre , Animales , Concanavalina A/farmacología , Corticosterona/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Inmunidad/fisiología , Interleucina-1/sangre , Interleucina-6/sangre , Linfocitos/inmunología , Linfocitos/fisiología , Ratones , Ratones Endogámicos C3H , Bazo/citología , Bazo/efectos de los fármacos , Estrés Psicológico/inmunología
15.
Mol Psychiatry ; 7(5): 468-73, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-12082564

RESUMEN

Cytokine therapy for cancer or viral diseases is accompanied by the development of depressive symptoms in a significant proportion of patients. Despite the increasing number of studies on the neurotoxic effects of cytokines, the mechanisms by which cytokines induce depressive symptoms remain largely unknown. In view of the relationship between neurotransmitter precursors and mood, the present study aimed at assessing the relationship between serum concentrations of the amino acids tryptophan and tyrosine, major precursors of serotonin and norepinephrine respectively, and depressive symptoms in cancer patients undergoing cytokine therapy. Sixteen cancer patients eligible to receive immunotherapy with interleukin-2 and/or interferon-alpha participated in the study. At baseline and after one week and one month of therapy, depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), and blood samples were collected for the determination of the large neutral amino acids (LNAA) (tryptophan, tyrosine, valine, leucine, isoleucine, phenylalanine) which compete for transport across the blood-brain barrier. Serum concentrations of tryptophan as well as the tryptophan/LNAA ratio significantly decreased between baseline, one week and one month of therapy. The development and severity of depressive symptoms, especially anorexia, pessimistic thoughts, suicidal ideation and loss of concentration were positively correlated with the magnitude of the decreases in tryptophan concentrations during treatment. These findings indicate that the development of depressive symptoms in patients undergoing cytokine therapy could be mediated by a reduced availability of the serotonin relevant amino acid precursor, tryptophan.


Asunto(s)
Citocinas/uso terapéutico , Trastorno Depresivo/sangre , Interferón-alfa/uso terapéutico , Interleucina-2/uso terapéutico , Neoplasias/psicología , Triptófano/sangre , Adulto , Anciano , Biomarcadores/sangre , Barrera Hematoencefálica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Análisis de Regresión , Factores de Tiempo
16.
Neuroreport ; 12(18): 3979-83, 2001 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-11742223

RESUMEN

Systemic administration of the bacterial endotoxin lipopolysaccharide (LPS) has profound depressive effects on behavior that are mediated by the inducible expression of proinflammatory cytokines such as interleukin-1 (IL-1), IL-6 and tumor necrosis factor-alpha (TNF-alpha) in the brain. To assess the regulatory effects of the anti-inflammatory cytokine IL-13 on LPS-induced sickness behavior, rats injected i.p. with LPS were administered rat recombinant IL-13 i.c.v. IL-13 (300 ng) potentiated the behavioral effects of LPS (125 microg/kg) when both molecules were co-injected. Administration of IL-13 (300 ng) 12 h prior to LPS (150 microg/kg) did not block the depressing effects of LPS on social exploration. These results indicate that IL-13 acts as a proinflammatory cytokine in the brain.


Asunto(s)
Conducta Animal/efectos de los fármacos , Encéfalo/inmunología , Interleucina-13/farmacología , Lipopolisacáridos/farmacología , Animales , Sinergismo Farmacológico , Inyecciones Intraperitoneales , Inyecciones Intraventriculares , Masculino , Ratas , Ratas Wistar , Conducta Social
17.
J Neurochem ; 79(4): 726-36, 2001 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11723165

RESUMEN

When activated by its ligand, the interleukin receptor type I (IL-1RI) transduces signals in cooperation with the IL-1 receptor accessory protein (IL-1RacP). In contrast, IL-1RII functions as a decoy receptor without participating in IL-1 signalling. Brain astrocytes are cellular targets of IL-1 and play a pivotal role in brain responses to inflammation. The regulation of IL-1 receptors on astrocytes by anti-inflammatory cytokines such as IL-4 and IL-10 has not been studied, despite its importance for understanding the way these cells respond to IL-1. Using RT-PCR, we first showed that the expression of IL-1RI and IL-1RII, but not IL-1RacP, mRNAs are up-regulated by IL-1 beta in a time-dependent manner. Using a radioligand binding technique, we then showed that astrocytes display an equivalent number of IL-1RI and IL-1RII. IL-1 beta decreases the number of IL-1RI binding sites, whereas it increases those of IL-1RII. IL-4 and IL-10 both up-regulate IL-1RII IL-1 beta-induced, but only IL-4 does so for IL-1RI. At the protein level, IL-4 and IL-10 dramatically reverse the ability of IL-1 beta to inhibit expression of IL-1RI but neither affects the ability of IL-1 beta to enhance the number of IL-1RII. Collectively, these results establish the existence of receptor cross-talk between pro- and anti-inflammatory cytokines on a critical type of cell that regulates inflammatory events in the brain.


Asunto(s)
Astrocitos/metabolismo , Interleucina-10/farmacología , Interleucina-1/farmacología , Interleucina-4/farmacología , Receptores de Interleucina-1/metabolismo , Animales , Astrocitos/citología , Astrocitos/efectos de los fármacos , Sitios de Unión/efectos de los fármacos , Unión Competitiva/efectos de los fármacos , Células Cultivadas , Proteína Accesoria del Receptor de Interleucina-1 , Ratones , Proteínas/genética , Proteínas/metabolismo , ARN Mensajero/metabolismo , Ensayo de Unión Radioligante , Receptor Cross-Talk/efectos de los fármacos , Receptor Cross-Talk/fisiología , Receptores de Interleucina-1/genética , Receptores Tipo I de Interleucina-1 , Receptores Tipo II de Interleucina-1 , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Regulación hacia Arriba/efectos de los fármacos
18.
J Immunol ; 167(8): 4436-42, 2001 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-11591769

RESUMEN

IL-10 is well known to be a potent inhibitor of the synthesis of proinflammatory cytokines, but noninflammatory hemopoietic cells also express IL-10Rs. Here we show that IL-10 directly affects progenitor myeloid cells by protecting them from death following the removal of growth factors. Murine factor-dependent cell progenitors cultured in the absence of growth factors were 43 +/- 1% apoptotic after 12 h. Addition of IL-10 at a concentration as low as 100 pg/ml significantly reduced the apoptotic population to 32 +/- 3%. At 10 ng/ml, IL-10 caused a 4-fold reduction in the apoptotic population (11 +/- 1%). The anti-apoptotic activity of IL-10 was significantly inhibited with a neutralizing IL-10R Ab. Factor-dependent cell progenitor promyeloid cells expressed functional IL-10Rs, as assessed by precipitation of a 110-kDa protein with an Ab to the IL-10R and by the ability of IL-10 to activate Jak1 and Tyk2 and to phosphorylate tyrosine 705 on Stat-3. IL-10 increased tyrosyl phosphorylation of insulin receptor substrate-2 and stimulated the enzymatic activity of both phosphatidylinositol 3'-kinase and Akt. The anti-apoptotic activity of IL-10 was blocked by inhibition of phosphatidylinositol 3'-kinase. Wortmannin and LY294002 also totally inhibited activation of extracellular signal-related kinase (ERK)1/2 by IL-10. Direct inhibition of ERK1/2 with the mitogen-activated protein kinase/ERK kinase inhibitor PD98059 partially, but significantly, impaired the anti-apoptotic activity of IL-10. These data establish that activation of the IL-10R promotes survival of progenitor myeloid cells. This survival-promoting activity is totally due to IL-10 stimulating the insulin receptor substrate-2/PI 3-kinase/Akt pathway, which increases the anti-apoptotic activity of ERK1/2.


Asunto(s)
Apoptosis , Interleucina-10/farmacología , Células Mieloides/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfoproteínas/metabolismo , Supervivencia Celular , Proteínas de Unión al ADN/metabolismo , Activación Enzimática , Proteínas Sustrato del Receptor de Insulina , Péptidos y Proteínas de Señalización Intracelular , Janus Quinasa 1 , MAP Quinasa Quinasa 1 , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Proteínas/metabolismo , Proteínas Proto-Oncogénicas , Proteínas Proto-Oncogénicas c-akt , Receptores de Interleucina/metabolismo , Receptores de Interleucina-10 , Factor de Transcripción STAT3 , Transactivadores/metabolismo
19.
Brain Res ; 915(2): 244-7, 2001 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-11595215

RESUMEN

The ability of the brain serotonergic system to mediate the effects of interleukin-1beta (IL-1beta) was investigated. Intracerebroventricular administration of IL-1beta induced a significant pyrogenic reaction, depression in social behaviour, loss of body weight and reduced food intake in rats. Pre-treatment with p-chlorphenylalanine, an inhibitor of serotonin synthesis, blocked the IL-1beta-induced decrease in food intake and loss of body weight, but failed to alter the temperature increase and the decrease in communicative activity.


Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Fenclonina/farmacología , Interleucina-1/farmacología , Antagonistas de la Serotonina/farmacología , Serotonina/biosíntesis , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Masculino , Ratas , Ratas Wistar , Serotonina/fisiología
20.
J Neuroimmunol ; 119(2): 151-65, 2001 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-11585617

RESUMEN

The cytokine tumor necrosis factor(alpha) (TNFalpha) and the hormone insulin-like growth factor-I (IGF-I) have both been shown to regulate inflammatory events in the central nervous system (CNS). This review summarizes the seemingly independent roles of TNFalpha and IGF-I in promoting and inhibiting neurodegenerative diseases. We then offer evidence that the combined effects of IGF-I and TNFalpha on neuronal survival can be vastly different when both receptors are stimulated simultaneously, as is likely to occur in vivo. We propose the framework of a molecular model of hormone-cytokine receptor cross talk in which disparate cell surface receptors share intracellular substrates that regulate neuronal survival.


Asunto(s)
Encefalopatías/inmunología , Encéfalo/inmunología , Factor I del Crecimiento Similar a la Insulina/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Animales , Humanos
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