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

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Abstract

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 factor-alpha (TNF-α) 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-α resulted in a dose- and time-dependent 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-α enhanced the transport capacity (Vmax) 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-α activates the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Pre-treatment with the p38 MAPK inhibitor SB203580 attenuated the TNF-α 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-α, an effect that is at least in part dependent on p38 MAPK activation.

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Acknowledgments

We thank Dr. Gethin McBean (University College Dublin, Ireland) for the C6 glioma cells. This work was supported by Grants from Science Foundation Ireland (SFI, Grant number BIM0033) and the Irish Health Research Board (HRB, Grant number HRA/2009/303) to J.H.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin 4, Ireland

    Sandra Malynn, Antonio Campos-Torres & Jana Haase

  2. Institute of Immunology, National University of Ireland Maynooth, Maynooth, Co., Kildare, Ireland

    Antonio Campos-Torres & Paul Moynagh

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  1. Sandra Malynn
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  2. Antonio Campos-Torres
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Correspondence to Jana Haase.

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Malynn, S., Campos-Torres, A., Moynagh, P. et al. The Pro-inflammatory Cytokine TNF-α Regulates the Activity and Expression of the Serotonin Transporter (SERT) in Astrocytes. Neurochem Res 38, 694–704 (2013). https://doi.org/10.1007/s11064-012-0967-y

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  • DOI: https://doi.org/10.1007/s11064-012-0967-y

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