Regulation of the Human Serotonin Transporter by Interleukin-1β

Ramamoorthy, Sammanda; Ramamoorthy, J. D.; Prasad, Puttur D.; Bhat, Ganapathy K.; Mahesh, Virendra B.; Leibach, Frederick H.; Ganapathy, Vadivel

doi:10.1006/bbrc.1995.2659

Cited by 158 publications

(89 citation statements)

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“…Previous studies using JAR choriocarcinoma cells have shown that longer-term exposure to either IL-1b (Ramamoorthy et al, 1995) or TNF-a (Mõssner et al, 1998) will increase 5-HT uptake via an increase in transporter density. These effects, however, required prolonged exposureF16 h in the case of IL-1b and 48 h in the case of TNF-a.…”

Section: Discussionmentioning

confidence: 95%

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

Zhu

Blakely

Hewlett

2006

Neuropsychopharmacol

482

317

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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 K m 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-1b) and tumor necrosis factor alpha (TNF-a) stimulated serotonin uptake in both the rat embryonic raphe cell line, RN46A, and in mouse midbrain and striatal synaptosomes. In RN46A cells, IL-1b 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 mM), a p38 MAPK inhibitor. TNF-a also dose-and time-dependently stimulated 5-HT uptake that was only partially blocked by SB203580. Western blots showed that IL-1b and TNF-a activated p38 MAPK, in an SB203580-sensitive manner. IL-1b induced an SB203580-sensitive decrease in 5-HT K m with no significant change in V max . In contrast, TNF-a stimulation decreased 5-HT K m and increased SERT V max . SB203580 selectively blocked the TNF-a-induced change in SERT K m . In mouse midbrain and striatal synaptosomes, maximal stimulatory effects on 5-HT uptake occurred at lower concentrations (IL-1b, 10 ng/ml; TNF-a, 20 ng/ml), and over shorter incubation times (10 min). As with RN46A cells, the effects of IL-1b and TNF-a were completely (IL-1b) or partially (TNF-a) 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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Section: Discussionmentioning

confidence: 95%

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

Zhu

Blakely

Hewlett

2006

Neuropsychopharmacol

482

317

View full text Add to dashboard Cite

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“…In JAR cells, exposure to IL-1b for up to 16 h has been shown to mediate changes in SERT activity, namely a dose-dependent increase in SERT mRNA, an increase in SERT cell surface density and consequently an imipramine sensitive increase in [ 3 H]5-HT uptake [24]. Studies conducted in the same cell line following treatment for up to 72 h with the pro-inflammatory cytokines TNF-a and IL-6 revealed that TNF-a but not IL-6 treatment resulted in an increase in the V max for 5-HT transport in these cells [25].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, pro-inflammatory cytokines have been implicated in the regulation of serotonergic homeostasis in vivo through the modulation of central serotonin activity and metabolism [20,21]. Studies assessing cytokine-mediated modulation of SERT expression and/or activity have predominately been conducted in SERT expressing cell lines of peripheral origin [4,[22][23][24][25][26]. Comparatively little is known about the mechanisms by which cytokines and other pro-inflammatory molecules may exert a functional influence on the transporter in cells of the central nervous system i.e.…”

Section: Introductionmentioning

confidence: 99%

The Pro-inflammatory Cytokine TNF-α Regulates the Activity and Expression of the Serotonin Transporter (SERT) in Astrocytes

et al. 2013

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Pro-inflammatory cytokines have been implicated in the precipitation of depression and related disorders, and the antidepressant sensitive serotonin transporter (SERT) may be a major target for immune regulation in these disorders. Here, we focus on astrocytes, a major class of immune competent cells in the brain, to examine the effects of pro-longed treatment with tumor necrosis factoralpha (TNF-a) on SERT activity. We first established that high-affinity serotonin uptake into C6 glioma cells occurs through a SERT-dependent mechanism. Functional SERT expression is also confirmed for primary astrocytes. In both cell types, exposure to TNF-a resulted in a dose-and timedependent increase in SERT-mediated 5-HT uptake, which was sustained for at least 48 h post-stimulation. Further analysis in primary astrocytes revealed that TNF-a enhanced the transport capacity (V max ) of SERT-specific 5-HT uptake, suggesting enhanced transporter expression, consistent with our observation of an increase in SERT mRNA levels. We confirmed that in both, primary astrocytes and C6 glioma cells, treatment with TNF-a activates the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Pre-treatment with the p38 MAPK inhibitor SB203580 attenuated the TNF-a mediated stimulation of 5-HT transport in both, C6 glioma and primary astrocytes. In summary, we show that SERT gene expression and activity in astrocytes is subject to regulation by TNF-a, an effect that is at least in part dependent on p38 MAPK activation.

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“…226,228 Moreover, it has been suggested that proinflammatory cytokines result in reduced extracellular 5-HT levels 208,229-231 based on the finding that several proinflammatory cytokines have been shown to upregulate 5-HTT expression. [232][233][234] Ultimately, neurotrophic factors such as brain derived neurotrophic factor (BDNF) may be affected. The activation of proinflammatory cytokines and/or inhibition of anti-inflammatory may be involved in depression by means of processes related to neuroplasticity.…”

Section: Stressmentioning

confidence: 99%

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

et al. 2006

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In recent years, the term serotonergic vulnerability (SV) has been used in scientific literature, but so far it has not been explicitly defined. This review article attempts to elucidate the SV concept. SV can be defined as increased sensitivity to natural or experimental alterations of the serotonergic (5-HTergic) system. Several factors that may disrupt the 5-HTergic system and hence contribute to SV are discussed, including genetic factors, female gender, personality characteristics, several types of stress and drug use. It is explained that SV can be demonstrated by means of manipulations of the 5-HTergic system, such as 5-HT challenges or acute tryptophan depletion (ATD). Results of 5-HT challenge studies and ATD studies are discussed in terms of their implications for the concept of SV. A model is proposed in which a combination of various factors that may compromise 5-HT functioning in one person can result in depression or other 5-HT-related pathology. By manipulating 5-HT levels, in particular with ATD, vulnerable subjects may be identified before pathology initiates, providing the opportunity to take preventive action. Although it is not likely that this model applies to all cases of depression, or is able to identify all vulnerable subjects, the strength of the model is that it may enable identification of vulnerable subjects before the 5-HT related pathology occurs. Molecular Psychiatry ( Keywords: serotonin; mood disorders; stress; genetics; sex; tryptophan Involvement of serotonin in depressionMood disorders are one of the most prevalent forms of mental illness. 1 According to the DSM-IV, the lifetime risk for major depressive disorder is between 10 and 25% for women and between 5 and 12% for men. 2 Depression has been studied intensively during the last few decades, but the psychological and neurobiological determinants of depression have not yet been precisely defined. Although several factors are known to contribute to the etiology of depression, it is not clear how these factors cause depression, and why some subjects become depressed while others remain unaffected. In terms of biological factors in the etiology of depression, there are several hypotheses. These include neurotransmitter dysfunctions (serotonin, 5-HT; dopamine, DA; norepinephrine, NE); dysregulations in hypothalamic-pituitary-adrenal (HPA) axis activity; and immune system imbalance. The aim of this article is not to discuss all of these hypotheses in detail, but to evaluate the role that serotonin may play within these hypothesized mechanisms.It is widely accepted that diminished serotonergic (5-HTergic) function is involved in the onset and course of depression. 3,4 The 5-HTergic system is a large and complex system. Although nearly all cell bodies of 5-HTergic neurons are located in the raphe nuclei in the brain stem, the axons of these neurons innervate almost the entire brain. The actions of 5-HT are mediated by 16 types and subtypes of receptors. 5 As the 5-HTergic system is assumed to be a modulatory system, the exact func...

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Regulation of the Human Serotonin Transporter by Interleukin-1β

Cited by 158 publications

References 0 publications

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

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

The Pro-inflammatory Cytokine TNF-α Regulates the Activity and Expression of the Serotonin Transporter (SERT) in Astrocytes

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

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