Cited by 549Tryptophan and brain disordersNeurotransmitter Receptor Influence on BehaviorTreatment of Major Depression

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The Proinflammatory Cytokines Interleukin-1beta and Tumor Necrosis Factor-Alpha Activate Serotonin Transporters

Zhu, Chong-Bin, Blakely, Randy D, Hewlett, William A·2006·Neuropsychopharmacology

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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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Authors: Zhu, C.-B., Blakely, R. D., & Hewlett, W. A.
Affiliations: Vanderbilt University (US)
Corresponding author: Hewlett, William A
ORCID: Zhu, Chong-Bin
Blakely, Randy D
Venue: Neuropsychopharmacology
Publisher: Springer Science and Business Media LLC
Published: 2006-02-01
Volume: 31
Issue: 10
Pages: 2121-2131
ISSN: 0893-133X (ISSN-L)
1740-634X
DOI: 10.1038/sj.npp.1301029
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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The Proinflammatory Cytokines Interleukin-1beta and Tumor Necrosis Factor-Alpha Activate Serotonin Transporters

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