The Proinflammatory Cytokines Interleukin-1beta and Tumor Necrosis Factor-Alpha Activate Serotonin Transporters

Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-8645, USA.
Neuropsychopharmacology (Impact Factor: 7.05). 11/2006; 31(10):2121-31. DOI: 10.1038/sj.npp.1301029
Source: PubMed


Proinflammatory cytokines and serotonergic homeostasis have both been implicated in the pathophysiology of major psychiatric disorders. We have demonstrated that activation of p38 mitogen-activated protein kinase (MAPK) induces a catalytic activation of the serotonin transporter (SERT) arising from a reduction in the SERT Km for 5-hydroxytryptamine (5-HT). As inflammatory cytokines can activate p38 MAPK, we hypothesized that they might also activate neuronal SERT. Indeed, Interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) stimulated serotonin uptake in both the rat embryonic raphe cell line, RN46A, and in mouse midbrain and striatal synaptosomes. In RN46A cells, IL-1beta stimulated 5-HT uptake in a dose- and time-dependent manner, peaking in 20 min at 100 ng/ml. This was abolished by IL-1ra (20 ng/ml), an antagonist of the IL-1 receptor, and by SB203580 (5 microM), a p38 MAPK inhibitor. TNF-alpha also dose- and time-dependently stimulated 5-HT uptake that was only partially blocked by SB203580. Western blots showed that IL-1beta and TNF-alpha activated p38 MAPK, in an SB203580-sensitive manner. IL-1beta induced an SB203580-sensitive decrease in 5-HT Km with no significant change in Vmax. In contrast, TNF-alpha stimulation decreased 5-HT Km and increased SERT Vmax. SB203580 selectively blocked the TNF-alpha-induced change in SERT Km. In mouse midbrain and striatal synaptosomes, maximal stimulatory effects on 5-HT uptake occurred at lower concentrations (IL-1beta, 10 ng/ml; TNF-alpha, 20 ng/ml), and over shorter incubation times (10 min). As with RN46A cells, the effects of IL-1beta and TNF-alpha were completely (IL-1beta) or partially (TNF-alpha) blocked by SB203580. These results provide the first evidence that proinflammatory cytokines can acutely regulate neuronal SERT activity via p38 MAPK-linked pathways.

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    • "Our findings are in keeping with preclinical studies that have shown an association between TNF-a and 5-HTT. TNF-a treatment is associated with increases in MAPK-dependent 5-HTT uptake capacity, maximum uptake velocity and mRNA expression (Malynn et al., 2013; Mossner et al., 1998; Zhu et al., 2006). These changes have been associated with behaviour consistent with 'sickness behaviour' in rodent models (Zhu et al., 2010). "
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    ABSTRACT: Preclinical studies demonstrate that pro-inflammatory cytokines increase serotonin transporter availability and function, leading to depressive symptoms in rodent models. Herein we investigate associations between circulating inflammatory markers and brainstem serotonin transporter (5-HTT) availability in humans. We hypothesised that higher circulating inflammatory cytokine concentrations, particularly of tumour necrosis factor (TNF-α), would be associated with greater 5-HTT availability, and that TNF-α inhibition with etanercept (sTNFR:Fc) would in turn reduce 5-HTT availability. In 13 neurologically healthy adult women, plasma TNF-α correlated significantly with 5-HTT availability (rho=0.6; p=0.03) determined by [(123)I]-beta-CIT SPECT scanning. This association was replicated in an independent sample of 12 patients with psoriasis/psoriatic arthritis (rho=0.76; p=0.003). Indirect effects analysis, showed that there was a significant overlap in the variance explained by 5-HTT availability and TNF-α concentrations on BDI scores. Treatment with etanercept for 6-8weeks was associated with a significant reduction in 5-HTT availability (Z=2.09; p=0.03; r=0.6) consistent with a functional link. Our findings confirm an association between TNF-α and 5-HTT in both the basal physiological and pathological condition. Modulation of both TNF-α and 5-HTT by etanercept indicate the presence of a mechanistic pathway whereby circulating inflammatory cytokines are related to central nervous system substrates underlying major depression. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 08/2015; DOI:10.1016/j.bbi.2015.08.005 · 5.89 Impact Factor
    • "An inflammatory model of major depressive disorder (MDD) is also supported by other lines of evidence including increased levels of pro-inflammatory cytokines in MDD (Maes et al. 2012) and the common finding of the proinflammatory cytokine interferon alpha inducing MDD when used therapeutically (Udina et al. 2012). The mechanisms proposed to underlie interferon alpha-induced MDD include up-regulation of the central serotonin transporter molecule (Zhu et al. 2006), a decrease in neurogenesis in brain neuronal circuits regulating mood (Miller et al. 2009), activation of the enzyme indoleamine-d-oxygenase to divert tryptophan metabolism (Raison et al. 2010a), changes in central glutamate metabolism (Taylor et al. 2014), activation of the hypothalamic–pituitary–adrenal (HPA) axis (Eccles et al. 2012; Raison et al. 2010b) and alteration in cellular apoptosis mechanisms (Ping et al. 2012). Antidepressants have effect in both treating interferon alpha-induced MDD (Baraldi et al. 2012) and in reducing the likelihood of depression emergence when used prophylactically (Ehret and Sobieraj 2014). "
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    ABSTRACT: Major depressive disorder is a common consequence of exposure to the pro-inflammatory cytokine interferon alpha, which is treated effectively with antidepressant medication. Antidepressant mode of action may conflict with interferon alpha's mechanism in treating hepatitis C however. The purpose of this study is to prospectively explore, in a large naturalistic cohort, whether antidepressant exposure influenced end of treatment response of hepatitis C to interferon alpha. Two hundred thirty-nine patients infected with chronic hepatitis C and due to receive treatment were recruited. All participants initiated peg-interferon-2-alpha 180 μg weekly sub-cutaneously plus oral ribavirin 800-1200 mg daily. Participants were assessed for DSM-IV major depression at baseline and four weekly during treatment. 32.6 % of the cohort was exposed to an antidepressant (serotonin-reuptake inhibitor: other categorised antidepressants 49:29). At baseline, 3.8 % had major depression and 55.2 % developed major depression during interferon alpha treatment. Exposure to an antidepressant not classified as a serotonin-reuptake inhibitor, of which all were norepinephrine-enhancing (OR 0.15, 95 % CI 0.04-0.60) and having a past history of psychiatric disorder (OR 4.41, 95 % CI 1.39-13.96) independently reduced the likelihood of end of treatment response. Serotonin-reuptake inhibitor exposure did not influence end of treatment response (OR 1.21, 95 % CI 0.35-4.19), neither did major depression at baseline (OR 2.31, 95 % CI 0.55-9.60) or during treatment (OR 0.69, 95 % CI 0.36-1.33). Our findings support a lack of conflict of therapeutic mechanism of serotonin-reuptake inhibitor antidepressants with interferon alpha in treating hepatitis C, which may include inflammatory influence. This appears not to be true for norepinephrine-enhancing antidepressant types and warrants investigation using more direct methods.
    Psychopharmacology 05/2015; DOI:10.1007/s00213-015-3956-4 · 3.88 Impact Factor
    • "Sickness behavior and depressive disorders, for instance, are linked to alterations in 5-HT signaling. In this vein, IL-1b or TNFa treatment stimulate 5-HT uptake through upregulation of the serotonin transporter (SERT), decreasing the concentration of 5-HT available to signal in the synapase (Zhu et al., 2006). At the same time, these cytokines decrease the level of 5-HT receptor (5-HT 2A ) present on neurons, escalating the loss of 5-HT signaling and likely mediating the alterations to behavior (Cai et al., 2005) (Figure 3). "
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    ABSTRACT: Animals share an intimate and life-long partnership with a myriad of resident microbial species, collectively referred to as the microbiota. Symbiotic microbes have been shown to regulate nutrition and metabolism and are critical for the development and function of the immune system. More recently, studies have suggested that gut bacteria can impact neurological outcomes-altering behavior and potentially affecting the onset and/or severity of nervous system disorders. In this review, we highlight emerging evidence that the microbiome extends its influence to the brain via various pathways connecting the gut to the central nervous system. While understanding and appreciation of a gut microbial impact on neurological function is nascent, unraveling gut-microbiome-brain connections holds the promise of transforming the neurosciences and revealing potentially novel etiologies for psychiatric and neurodegenerative disorders. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell host & microbe 05/2015; 17(5):565-576. DOI:10.1016/j.chom.2015.04.011 · 12.33 Impact Factor
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