A Meta-Analysis of Cytokines in Major Depression

Dowlati, Yekta; Herrmann, Nathan; Swardfager, Walter; Liu, Helena; Sham, Lauren; Reim, Elyse K.; Lanctôt, Krista L.

doi:10.1016/j.biopsych.2009.09.033

Cited by 3,970 publications

(2,938 citation statements)

References 211 publications

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“…As reported elsewhere, in cellular assays of potency to block tryptophan-to-KYN conversion, the in vitro 50 % inhibitory concentration (IC 50 ) on murine IDO1 was 50 nM (Liu et al, 2010). For murine IDO2 IC 50 was >5000 nM and for 9 human TDO2 it was >10000 nM; therefore, in vitro selectivity of IDOInh for IDO1 relative to IDO2 was >100 and relative to TDO2 was >200 (Liu et al, 2010). In an in-house cellular assay, IC 50 on murine IDO1 was 390 nM.…”

Section: Indoleamine 23-dioxygenase Inhibitorsupporting

confidence: 60%

“…A small-molecule, potent (both human and murine) and selective inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) (hereafter IDOInh) (see (Liu et al, 2010;Yue et al, 2009) and (Cathomas et al, 2015)) was used. As reported elsewhere, in cellular assays of potency to block tryptophan-to-KYN conversion, the in vitro 50 % inhibitory concentration (IC 50 ) on murine IDO1 was 50 nM (Liu et al, 2010).…”

Section: Indoleamine 23-dioxygenase Inhibitormentioning

confidence: 99%

“…Acute psychosocial stress increases blood levels of chemokines and cytokines (Bierhaus et al, 2003), and chronic psychosocial stress leads to sensitization of stress inflammatory responses (Rohleder, 2014). MDD is associated with increased blood levels of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-) and interleukin-6 (IL-6) (Dowlati et al, 2010). MDD patients exhibit up-regulation of TNF and other inflammation genes in peripheral blood mononuclear cells; the expression levels of these genes correlate with amygdala reactivity to fearful faces (Savitz et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Fuertig

Azzinnari

Bergamini

et al. 2016

Brain, Behavior, and Immunity

115

125

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Psychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immuneinflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity to aversive stimuli. The present mouse study investigated effects of psychosocial stress as chronic social defeat (CSD) versus control-handling (CON) on: Pavlovian tone-shock fear conditioning, activation of the kynurenine pathway, and efficacy of a specific inhibitor (IDOInh) of the tryptophan-kynurenine catabolizing enzyme indoleamine 2,3-dioxygenase (IDO1), in reversing CSD effects on the kynurenine pathway and fear. CSD led to excessive fear learning and memory, whilst repeated oral escitalopram (antidepressant and anxiolytic) reversed excessive fear memory, indicating predictive validity of the model. CSD led to higher blood levels of TNF-, IFN-, kynurenine (KYN), 3-hydroxykynurenine (3-HK) and kynurenic acid, higher KYN and 3-HK in amygdala and hippocampus. However, CSD was without effect on IDO1 gene or protein expression in spleen, ileum and liver, whilst increasing liver TDO2 gene expression. Nonetheless, oral IDOInh reduced blood and brain levels of KYN and 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyper-activity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders. ABSTRACTPsychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immune-inflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyperactivity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders.3

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Section: Indoleamine 23-dioxygenase Inhibitorsupporting

confidence: 60%

Section: Indoleamine 23-dioxygenase Inhibitormentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Fuertig

Azzinnari

Bergamini

et al. 2016

Brain, Behavior, and Immunity

115

125

View full text Add to dashboard Cite

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“…Increases of the circulating cytokines interleukin (IL)-6 and tumor necrosis factor alpha (TNF), their soluble receptors, and the acute phase protein, C-reactive protein (CRP), have been reported (Dowlati et al, 2010); for review see: (Felger and Lotrich, 2013;Miller et al, 2009). Moreover, gene expression profiling conducted on post-mortem brain tissue samples from the frontal cortex of patients with MDD shows an upregulated expression of cytokines including eg IL-1, IL-18, IL-8, IL-12, lymphotoxin alpha and interferon (IFN)- (Shelton et al, 2011).…”

mentioning

confidence: 99%

Depression in Autoimmune Diseases

Pryce

Fontana

2016

Current Topics in Behavioral Neurosciences

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Up to 50% of patients with autoimmune diseases show an impairment of health-related quality of life and exhibit depression-like symptoms. The immune system not only leads to inflammation in affected organs, but also mediates behavior abnormalities including fatigue and depression-like symptoms. This review focuses on the different pathways involved in the communication of the immune system with the neuronal network and the body's timing system. The latter is built up by a hierarchically organized expression of clock genes. As discussed here, the activation of the immune system interferes with high amplitude expression of clock genes, an effect which may play a pivotal role in depression-like behavior in autoimmune diseases.

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“…Later studies demonstrated an important role for TNFα in mediating systemic inflammation based on its ability to mediate lethal endotoxin poisoning and lethal septic shock [21–23]. The production of this cytokine is deregulated in variety of human diseases including malignancies [24], Alzheimer’s disease [25], major depression [26] and inflammatory bowel disease (IBD) [27]. TNFα production is tightly controlled by both transcriptional and post-transcriptional mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Mnk kinases in cytokine signaling and regulation of cytokine responses

Joshi¹,

Platanias²

2012

Biomolecular Concepts

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The kinases Mnk1 and Mnk2 are activated downstream of the p38 MAPK and MEK/ERK signaling pathways. Extensive work over the years has shown that these kinases control phosphorylation of the eukaryotic initiation factor 4E (eIF4E) and regulate engagement of other effector elements, including hnRNPA1 and PSF. Mnk kinases are ubiquitously expressed and play critical roles in signaling for various cytokine receptors, while there is emerging evidence that they have important functions as mediators of pro-inflammatory cytokine production. In this review the mechanisms of activation of MNK pathways by cytokine receptors are addressed and their roles in diverse cytokine-dependent biological processes are reviewed. The clinical-translational implications of such work and the relevance of future development of specific MNK inhibitors for the treatment of malignancies and auto-immune disorders are discussed.

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A Meta-Analysis of Cytokines in Major Depression

Cited by 3,970 publications

References 211 publications

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Depression in Autoimmune Diseases

Mnk kinases in cytokine signaling and regulation of cytokine responses

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