title: The pro-inflammatory cytokine TNF-α regulates the activity and expression of the serotonin transporter (SERT) in astrocytes.
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.
authors: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin 4, Ireland.
authors: Sandra
authors: S
authors: Malynn
authors: Antonio
authors: A
authors: Campos-Torres
authors: Paul
authors: P
authors: Moynagh
authors: Jana
authors: J
authors: Haase
mesh_terms: D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D015283:Citalopram / Q000494:pharmacology; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D005910:Glioma / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D017374:Paroxetine / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000096:biosynthesis* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D007093:Imidazoles; D011725:Pyridines; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D014409:Tumor Necrosis Factor-alpha; D005473:Fluoxetine; D015283:Citalopram; C011386:nisoxetine; D012701:Serotonin; D017374:Paroxetine; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580