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The Proinflammatory Cytokines Interleukin-1beta and Tumor Necrosis Factor-Alpha Activate Serotonin Transporters
Abstract
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 Km 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-1beta) and tumor necrosis factor alpha (TNF-alpha) stimulated serotonin uptake in both the rat embryonic raphe cell line, RN46A, and in mouse midbrain and striatal synaptosomes. In RN46A cells, IL-1beta 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 microM), a p38 MAPK inhibitor. TNF-alpha also dose- and time-dependently stimulated 5-HT uptake that was only partially blocked by SB203580. Western blots showed that IL-1beta and TNF-alpha activated p38 MAPK, in an SB203580-sensitive manner. IL-1beta induced an SB203580-sensitive decrease in 5-HT Km with no significant change in Vmax. In contrast, TNF-alpha stimulation decreased 5-HT Km and increased SERT Vmax. SB203580 selectively blocked the TNF-alpha-induced change in SERT Km. In mouse midbrain and striatal synaptosomes, maximal stimulatory effects on 5-HT uptake occurred at lower concentrations (IL-1beta, 10 ng/ml; TNF-alpha, 20 ng/ml), and over shorter incubation times (10 min). As with RN46A cells, the effects of IL-1beta and TNF-alpha were completely (IL-1beta) or partially (TNF-alpha) 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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“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 Zhu et al., 2006
In the citing paper
“Cytokines also influence the synthesis of monoamines through disruption of tetrahydrobiopterin, an essential enzyme co-factor to hydroxylases involved in monoamine synthesis.”
From Cytokine Research in Depression: Principles, Challenges, and Open Questions (2019) · cites this paper as [89]
In the citing paper
“Furthermore, they can modulate serotonin signaling by increasing the expression and function of monoamine transporters which perform the re-uptake of synaptic serotonin (89–92).”
From Cytokine Research in Depression: Principles, Challenges, and Open Questions (2019) · cites this paper as [89]
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Metadata
- Authors
- Zhu, C.-B., Blakely, R. D., & Hewlett, W. A.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Hewlett, William A
- Venue
- Neuropsychopharmacology
- Published
- 2006-02-01
- Volume
- 31
- Issue
- 10
- Pages
- 2121-2131
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- OpenAlex
- W2065313926
- Cited by
- 549
- References
- 63
- Citations by year
- 2026: 14 · 2025: 19 · 2024: 21 · 2023: 32 · 2022: 32 · 2021: 34 · 2020: 30 · 2019: 31 · 2018: 28 · 2017: 21 · 2016: 33 · 2015: 38 · 2014: 38 · 2013: 40 · 2012: 37
- FWCI
- 5.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institute on Drug Abuse (DA-07390, R01DA007390)
- 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 (medical) › Treatment of Major Depression
- Keywords
- serotonin transporter, IL-1β, TNF-α, inflammatory cytokines, p38 MAPK, serotonin uptake, serotonin, neuroinflammation, interleukin-1 receptor antagonist, SB203580, synaptosomes, midbrain, striatum
- MeSH terms
- Analysis of Variance, Animals, Cell Line, Corpus Striatum, Dose-Response Relationship, Drug, Drug Interactions, Enzyme Activation, Enzyme Inhibitors, Interleukin-1, Mesencephalon, Neurons, Raphe Nuclei, Serotonin, Synaptosomes, Tumor Necrosis Factor-alpha, p38 Mitogen-Activated Protein Kinases, Serotonin Plasma Membrane Transport Proteins, Mice, Rats
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