Analysis of IL-1α, IL-1β, and IL-RA Polymorphisms in Dysthymia

Fertuzinhos, Sofia; Oliveira, João Ricardo Mendes de; Nishimura, Agnes L.; Pontual, Deyse; Carvalho, Daniel Resende; Sougey, Éverton Botelho; Otto, Paulo Alberto; Zatz, Mayana

doi:10.1385/jmn:22:3:251

Cited by 39 publications

(22 citation statements)

References 31 publications

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“…Certain cytokine gene polymorphisms, for example, in genes coding for IL-1 and TNF-a, may confer a greater susceptibility to develop MD. [81][82][83] The production of IL-2 and IFN-g is the typical marker of a type 1 immune response. IFN-g is produced in greater amounts by lymphocytes of patients with MD compared to healthy controls.…”

Section: The Inflammatory Hypothesis Of Depressionmentioning

confidence: 99%

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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Section: The Inflammatory Hypothesis Of Depressionmentioning

confidence: 99%

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

2007

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“…Motivated by the previous interest of our group in genetic polymorphisms of the Interleukin-1 panel in AD and Mood Disorders, we selected genes from an expression microarray study in hippocampus of affected patients which infers that the up-regulation of IL-1α, IL-1β, COX-2, PLA2G4A, and CD83 genes could be due to the inflammatory process, neurotoxicity and cell death (Colangelo et al 2002;Fertuzinhos et al 2004;Oliveira et al 2009). …”

Section: Introductionmentioning

confidence: 99%

In Silico Identification of New Genetic Variations as Potential Risk Factors for Alzheimer’s Disease in a Microarray-oriented Simulation

et al. 2009

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Genomic and proteomic studies of neurodegenerative disorders require complementary approaches to integrate the massive amount of data generated in high throughput experimental procedures. We propose a Bioinformatics pipeline in which expression studies guide the selection of candidate genes that should be screened for potential new genetic variations from a public expressed site tags (ESTs) database. Motivated by the former interest of our group in genetic polymorphisms involved with the immune system, we selected five genes from a previous expression microarrays study of hippocampal cornu ammonis (CA1) area of Alzheimer's Disease subjects (AD). The CLCbio Workbench Combined version 3.6.2. was initially used to build ESTs and mRNA files retrieved respectively from the Goldenpath of University of California Santa Cruz (UCSC) and National Center for Biotechnology Information (NCBI) databases and latter to perform multiple batches of Smith-Waterman alignments. A total of 116 ESTs sequences were selected after proper stringent parameters were applied to the first set of mismatches. The annotation revealed various classes of variations, most of them deletions (176). Amongst this specific group, some were frameshift deletions (35) and the virtual translation of a few others (5) were predicted to induce no change other than a single aminoacid removal, with no subsequent repercussions at the protein sequence. In addition, the analysis identified transitions (three), transversions (52), synonymous (41), non-synonymous (12), and deletions in 36 ESTs located in Untranslated Regions -UTRs (Supplementary data). Deletions are often associated to major genetics syndromes with dysmorphic features. However, various recent studies show that common microdeletions might be highly associated with common neuropsychiatric disorders such as schizophrenia, autism, mental retardation, or even in various ethnicities, detected in whole genome sequencing experiments. A virtual validation confirmed that some of the variations identified were previously reported and confirmed in DNA samples, showing that this method is a feasible way to detect genetic variations that merit further exploration in AD genetic risk factor association studies.

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“…Based on these observations, the genetics of the immune system in relation to mood disorders has been investigated. The genetic susceptibility to mood disorders might be explained by the presence of specific polymorphisms in cytokine genes leading to abnormal protein expression or functioning [17,18] .…”

mentioning

confidence: 99%

The MCP-1 Gene (SCYA2) and Mood Disorders: Preliminary Results of a Case-Control Association Study

Ac¹,

Mundo²,

Cattaneo³

et al. 2009

Neuroimmunomodulation

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The aim of this case-control study was to investigate the potential role of the A-2518G polymorphism of the gene of monocyte chemoattractant protein 1 (MCP-1, a cytokine playing an important role in innate immunity) in conferring susceptibility to mood disorders. The sample studied included 96 outpatients with DSM-IV-TR diagnosis of major depressive disorder, bipolar disorder I (BD I) or BD II and 161 matched healthy controls. All subjects were genotyped for the A-2518G polymorphism of the MCP-1 gene. Genotypic and allelic associations were explored between patients and controls and across the different diagnostic groups (χ² tests). No genotypic (χ² = 8.215, d.f. = 6, p = 0.223) or allelic (χ² = 5.058, d.f. = 3, p = 0.168) association for the A-2518G polymorphism of SCYA2 was found considering cases and controls. Nevertheless, important correlations were observed when patients were divided into diagnostic subgroups. A significantly higher frequency of the AA genotype (χ² = 7.233, d.f. = 2, p = 0.027) and of the A allele (χ² = 4.730, d.f. = 1, p = 0.030) was observed in subjects with BD. In addition, independently from diagnosis, a higher number of lifetime suicide attempts was found in subjects with the AA genotype of the A-2518G polymorphism of the MCP-1 gene (F = 3.802, p = 0.026). The present preliminary results, though limited by the relatively small sample, suggest a possible role of the SCYA2 in conferring susceptibility to BD and, if confirmed, may represent a biological discriminative influence between mood disorder subtypes.

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Analysis of IL-1α, IL-1β, and IL-RA Polymorphisms in Dysthymia

Cited by 39 publications

References 31 publications

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

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

In Silico Identification of New Genetic Variations as Potential Risk Factors for Alzheimer’s Disease in a Microarray-oriented Simulation

The MCP-1 Gene (SCYA2) and Mood Disorders: Preliminary Results of a Case-Control Association Study

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