The DOI matches its Crossref record; 62 of the 63 references it cites were found in a registry or an index.
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Citations
Cites
Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., McClay, J., Mill, J., Martin, J., Braithwaite, A., et al. (2003) · Science · doi:10.1126/science.1083968 · Cited by 8,120
Psychopharmacology: The Fourth Generation of Progress
Bloom, F. E., & Kupfer, D. J. (1995) · Medical Entomology and Zoology · Cited by 2,985
Cytokines and major depression
Schiepers, O. J. G., Wichers, M. C., & Maes, M. (2005) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2004.11.003 · Cited by 1,235
Differential Regulation of AMPA Receptor and GABA Receptor Trafficking by Tumor Necrosis Factor-α
Stellwagen, D., Beattie, E. C., Seo, J. Y., & Malenka, R. C. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.4486-04.2005 · Cited by 985 · cited 1×
“Similarly, short-term exposure of hippocampal neurons to TNF-a (15–30 min) has been found to induce endocytosis of GABA-A receptors and increase trafficking of excitatory AMPA receptors to the plasma membrane (Stellwagen et al, 2005).”
BackgroundcDNA Expression Cloning of the IL-1 Receptor, a Member of the Immunoglobulin Superfamily
Sims, J. E., March, C. J., Cosman, D. J., Widmer, M. B., MacDonald, H. R., McMahan, C. J., Grubin, C. E., Wignall, J. M., Jackson, J. L., Call, S. M., et al. (1988) · Science · doi:10.1126/science.2969618 · Cited by 877
Cytokine‐Induced Sickness Behavior: Mechanisms and Implications
Dantzer, R. (2001) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2001.tb05827.x · Cited by 825
Psychopharmacology: The Fourth Generation of Progress
Kramlinger, K. G. (1995) · Mayo Clinic Proceedings · doi:10.4065/70.10.1021-a · Cited by 779
Interleukin-1 Immunoreactive Innervation of the Human Hypothalamus
Breder, C. D., Dinarello, C. A., & Saper, C. B. (1988) · Science · doi:10.1126/science.3258444 · Cited by 755
Brockhaus, M., Schönfeld, H., Schlaeǵer, E.-J., Hunziker, W. H., Lesslauer, W., & Loetscher, H. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.8.3127 · Cited by 649
Li, Y.-P., Chen, Y., John, J., Moylan, J. S., Jin, B., Mann, D. L., & Reid, M. B. (2005) · The FASEB Journal · doi:10.1096/fj.04-2364com · Cited by 634
Flagged first, then by citations
1 of the 63 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
From inflammation to sickness and depression: when the immune system subjugates the brain
Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2297 · Cited by 7,395
Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression
Miller, A. H., Maletic, V., & Raison, C. L. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.11.029 · Cited by 3,848
Raison, C. L., Rutherford, R. E., Woolwine, B. J., Shuo, C., Schettler, P., Drake, D. F., Haroon, E., & Miller, A. H. (2013) · JAMA Psychiatry · doi:10.1001/2013.jamapsychiatry.4 · Cited by 1,617
O'Connor, J. C., Lawson, M. A., André, C., Moreau, M., Lestage, J., Castanon, N., Kelley, K. W., & Dantzer, R. (2009) · Molecular Psychiatry · doi:10.1038/sj.mp.4002148 · Cited by 1,278
Immune system to brain signaling: Neuropsychopharmacological implications
Capuron, L., & Miller, A. H. (2011) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2011.01.014 · Cited by 1,195
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
