The pro-inflammatory cytokine TNF-α regulates the activity and expression of the serotonin transporter (SERT) in astrocytes

Sandra Malynn, Antonio Campos-Torres, Paul Moynagh, Jana Haase

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)694-704
Number of pages11
JournalNeurochemical Research
Volume38
Issue number4
DOIs
Publication statusPublished - Apr 2013

Keywords

  • Astrocytes
  • Cell Line, Tumor
  • Citalopram
  • Fluoxetine
  • Glioma
  • Humans
  • Imidazoles
  • Paroxetine
  • Pyridines
  • Serotonin
  • Serotonin Plasma Membrane Transport Proteins
  • Tumor Necrosis Factor-alpha
  • p38 Mitogen-Activated Protein Kinases
  • Journal Article
  • Research Support, Non-U.S. Gov't

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