Effects of interferon-α, interferon-γ and cAMP on the transcriptional regulation of the serotonin transporter
Abstract
We examined the effects of interferon-alpha and -gamma, which are known to have psychiatric side effects including depression, on the transcriptional regulation of the serotonin transporter and the uptake activity of the serotonin transporter in order to clarify the involvement of the serotonin transporter in the pathogenesis of interferon-induced depression. In human placental choriocarcinoma cells (BeWo cells), both messenger RNA (mRNA) for the serotonin transporter and the imipramine-sensitive uptake of serotonin were detected. The levels of serotonin transporter mRNA were increased by treatment with interferon-alpha and -gamma for 3 h. The increase in serotonin transporter mRNA elicited by the interferons was inhibited by treatment with actinomycin D, an inhibitor of transcription. Treatment with interferon-alpha or -gamma for 3-6 h, but not for 30 min, increased the uptake activity of the serotonin transporter. Treatment with dibutyryl cAMP (Dib-cAMP) which was reported to up-regulate the transcription of the serotonin transporter, also increased the mRNA levels and the activity of serotonin transporter in BeWo cells. The levels of serotonin transporter mRNA gradually increased after treatment with Dib-cAMP over 24 h, while the maximal increase in serotonin transporter mRNA elicited by the interferons was detected 3 h after the treatment. The level of serotonin transporter mRNA was increased both in the midbrain and adrenal glands of mice which were treated with interferons for 3 h. These results suggest that the interferon-induced psychiatric side effects arise through regulation of serotonin transporter transcription and that the transcriptional regulation of the serotonin transporter is a possible neurochemical mechanism of affective disorders.
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Inflammatory cytokines including IL-6 increase 5-HTT expression and function, an effect mediated by induction of p38 MAPK both in vitro and in vivo.
“Interestingly, inflammatory cytokines, including IL-6, have been shown to increase 5-HTT expression and function (Morikawa et al., 1998, Mossner et al., 1998, Sakai et al., 2003, Tsao et al., 2008) (see Figure 1), an effect found to be mediated by induction of p38 mitogen-activated protein kinase (MAPK), both in vitro and in vivo (Zhu et al., 2005, Zhu et al., 2006, Zhu et al., 2010a).”
From Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications (2013) · cites this paper as Morikawa et al., 1998
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“Moreover, it has been shown that IFN-a is a potent inducer of mitogen activated protein kinase (MAPK) signaling pathways [18], that have been reported to activate monoamine transporters and thereby deplete their synaptic concentrations [13,19].”
BackgroundResult
- Authors
- Morikawa, O., Sakai, N., Obara, H., & Saito, N.
- Affiliations
- Biosignal Research Center, Kobe University (JP)
- Kobe University (JP)
- Corresponding author
- Saito, Naoaki
- Venue
- European Journal of Pharmacology
- Publisher
- Elsevier BV
- Published
- 1998-05
- Volume
- 349
- Issue
- 2-3
- Pages
- 317-324
- ISSN
- 0014-2999 (ISSN-L)
- OpenAlex
- W2092395511
- Cited by
- 160
- References
- 38
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 1 · 2017: 2 · 2016: 5 · 2015: 9 · 2014: 9 · 2013: 10 · 2012: 4
- FWCI
- 1.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- interferon-alpha, interferon-gamma, serotonin transporter, transcriptional regulation, interferon-induced depression, dibutyryl cyclic AMP, serotonin uptake, BeWo cells, actinomycin D, midbrain, adrenal gland, psychiatric adverse effects, mood disorders
- MeSH terms
- Cyclic AMP, Animals, Carrier Proteins, Choriocarcinoma, HeLa Cells, Humans, Interferon-gamma, Male, Membrane Glycoproteins, Mesencephalon, Mice, Inbred BALB C, Nerve Tissue Proteins, Serotonin, Tumor Cells, Cultured, Gene Expression, Interferon-alpha, Membrane Transport Proteins, Serotonin Plasma Membrane Transport Proteins, Mice
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