Cerebrospinal Cytokine Levels in Patients with Acute Depression

Levine, Joseph; Barak, Yoram; Chengappa, K.N.R.; Rapoport, A.; Rebey, M.; Barak, Vivian

doi:10.1159/000026615

Cited by 311 publications

(194 citation statements)

References 26 publications

(36 reference statements)

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“…An extensive and thorough meta-analysis concluded that there was no consistent evidence for elevated IL-1 in the plasma of depressed patients [206]. However, an elevation of CSF IL-1 has been reported in a limited study [207], but this has not yet been confirmed. Nevertheless, it has been argued that sickness behavior in animals may be a model for depression [195][196][197].…”

Section: Implications Of Cytokine-induced Effects On Neuro-transmissimentioning

confidence: 98%

Effects of cytokines and infections on brain neurochemistry

Dunn

2006

Clinical Neuroscience Research

283

169

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Administration of cytokines to animals can elicit many effects on the brain, particularly neuroendocrine and behavioral effects. Cytokine administration also alters neurotransmission, which may underlie these effects. The most well studied effect is the activation of the hypothalamopituitary-adrenocortical (HPA) axis, especially that by interleukin-1 (IL-1). Peripheral and central administration of IL-1 also induces norepinephrine (NE) release in the brain, most markedly in the hypothalamus. Small changes in brain dopamine (DA) are occasionally observed, but these effects are not regionally selective. IL-1 also increases brain concentrations of tryptophan, and the metabolism of serotonin (5-HT) throughout the brain in a regionally nonselective manner. Increases of tryptophan and 5-HT, but not NE, are also elicited by IL-6, which also activates the HPA axis, although it is much less potent in these respects than IL-1. IL-2 has modest effects on DA, NE and 5-HT. Like IL-6, tumor necrosis factor-α (TNFα) activates the HPA axis, but affects NE and tryptophan only at high doses. The interferons (IFN's) induce fever and HPA axis activation in man, but such effects are weak or absent in rodents. The reported effects of IFN's on brain catecholamines and serotonin have been very varied. However, interferon-γ, and to a lesser extent, interferon-α, have profound effects on the catabolism of tryptophan, effectively reducing its concentration in plasma, and may thus limit brain 5-HT synthesis.Administration of endotoxin (LPS) elicits responses similar to those of IL-1. Bacterial and viral infections induce HPA activation, and also increase brain NE and 5-HT metabolism and brain tryptophan. Typically, there is also behavioral depression. These effects are strikingly similar to those of IL-1, suggesting that IL-1 secretion, which accompanies many infections, may mediate these responses. Studies with IL-1 antagonists, support this possibility, although in most cases the antagonism is incomplete, suggesting the existence of multiple mechanisms. Because LPS is known to stimulate the secretion of IL-1, IL-6 and TNFα, it seems likely that these cytokines mediate at least some of the responses, but studies with antagonists indicate that there are multiple mechanisms. The neurochemical responses to cytokines are likely to underlie the endocrine and behavioral responses. The NE response to IL-1 appears to be instrumental in the HPA activation, but other mechanisms exist. Neither the noradrenergic nor the serotonergic systems appear to be involved in the major behavioral responses. The significance of the serotonin response is unknown.

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Section: Implications Of Cytokine-induced Effects On Neuro-transmissimentioning

confidence: 98%

Effects of cytokines and infections on brain neurochemistry

Dunn

2006

Clinical Neuroscience Research

283

169

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“…88 According to the sickness behavior hypothesis, the cytokines TNF-a, IL-1 and IL-6 have frequently been investigated in MD. A considerable number of studies showed elevated serum levels of TNF-a 70,86,[89][90][91][92][93] and IL-1b [94][95][96] in depressed patients, whereas only few investigators reported unchanged levels of these cytokines. 97 A study on elevated mRNA levels of TNF-a in peripheral mononuclear cells of depressed patients confirms the majority of findings on elevated serum levels.…”

Section: The Inflammatory Hypothesis Of Depressionmentioning

confidence: 99%

“…98 Levels of IL-1b are also elevated in cerebrospinal fluid (CSF), whereas TNF-a levels are not altered in CSF of depressed patients. 89 As a product of activated monocytes and macrophages, IL-6 is one of the most frequently investigated immune parameters in MD. The majority of reports demonstrate a markedly higher in vitro IL-6 production, 80,94 or higher serum IL-6 levels in depressed patients 65,87,93,[99][100][101][102][103][104] as well as IL-6 mRNA expression in leukocytes.…”

Section: The Inflammatory Hypothesis Of Depressionmentioning

confidence: 99%

“…112 Another study investigating depressed patients of age 18-66 could not find any alteration of IL-6 levels in the CSF. 113 Levine et al 89 compared serum and CSF cytokine levels in depressed patients and healthy control persons and found significantly elevated serum levels of IL-6, but decreased IL-6 levels in CSF. Thus, the elevated IL-6 secretion may be restricted to the peripheral compartment.…”

Section: The Inflammatory Hypothesis Of Depressionmentioning

confidence: 99%

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The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

2007

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Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor activation as well. However, cause and interaction of these neurotransmitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, interferon-c, or tumor necrosis factor-a activate the tryptophan-and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes -counteracting this metabolism due to the lack of an enzyme of this metabolism -have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid. Molecular Psychiatry (2007) 12, 988-1000; doi:10.1038/sj.mp.4002006; published online 24 April 2007 Keywords: major depression; psychoneuroimmunology; IDO; glutamate; immune system; serotonin Glutamate in depressionGlutamatergic neurotransmission is involved in depression and interacts with the serotonergic and noradrenergic systems The common therapeutic mechanism of antidepressant drugs is the enhancement of serotonergic and/or noradrenergic neurotransmission. On the basis of this pharmacological profile of antidepressant drugs, neurochemical research on major depression ...

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“…The expression of PTX3 is inducible by IL-1b and tumor necrosis factor alpha (TNFa) in the brain , endothelial cells (Breviario et al, 1992), and fibroblasts Lee and Masson, 1993;Diaz et al, 2001). This may be significant given the extensive literature relating depression and immune dysfunction (Leonard, 2000); depressed patients have been shown to have significant elevations of cerebrospinal fluid levels of IL-1b, IL-6, and TNF-a, effects that are antagonized by antidepressants (Levine et al, 1999;Castanon et al, 2002). Although the exact function of PTX3 remains unknown, it has been shown to associate with apoptotic cells.…”

Section: Introductionmentioning

confidence: 99%

Differential Expression of Pentraxin 3 in Fibroblasts from Patients with Major Depression

Shelton

Shan

Peng

et al. 2003

Neuropsychopharmacol

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In this study, differential display technology was used to compare gene expression in cultured fibroblasts from patients with major depression, melancholic subtype vs nonmelancholic depressives and normal volunteer controls. Genes differentially expressed in depressives and normals included an overexpressed 269 bp sequence tag showing B95% identity with the Homo sapiens long pentraxin 3 (PTX3) gene sequence in the 3 0 noncoding region. The 269 bp complimentary DNA probe hybridized with the 1.9 kb PTX3 mRNA. The densitometric analysis of slot blots showed that the mean steady-state mRNA level of PTX3 was 3.5-fold higher in the melancholic group as compared to that in normal controls and in nonmelancholic depressives (n ¼ 8, all groups). Incubation experiments were then conducted: confluent fibroblasts from melancholics and normal volunteers were incubated with isoproterenol 1 mM, dexamethasone (DEX) 500 nM, and interleukin 1b (IL-1b) 50 ng/ml, for 0, 0.5, 1, 4, and 24 h. mRNA was isolated and quantitated using Northern blot analysis. Isoproterenol produced no significant change in PTX3 expression; DEX produced a significant increase at 4 and 24 h; IL-1b induced an increase in both the groups that peaked at 4 h, declining to near basal levels at 24 h. There were no differences between melancholics or controls in mean change or maximum response with either DEX or IL-1b. The results are consistent with the reported effects of IL-1b on PTX3 expression in mouse brain. The results are of potential importance because PTX3 is a member of the long pentraxin subfamily of acute-phase proteins, which is inducible by IL-1b, and may play roles in neuroimmunity and neuroprotection.

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Cerebrospinal Cytokine Levels in Patients with Acute Depression

Cited by 311 publications

References 26 publications

Effects of cytokines and infections on brain neurochemistry

Effects of cytokines and infections on brain neurochemistry

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

Differential Expression of Pentraxin 3 in Fibroblasts from Patients with Major Depression

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