Activation of Central Nervous System Inflammatory Pathways by Interferon-Alpha: Relationship to Monoamines and Depression

Charles L. Raison, Andrey S. Borisov, Matthias Majer, Daniel F. Drake, Giuseppe Pagnoni, Bobbi J. Woolwine, Gerald J. Vogt, Breanne Massung, Andrew H. Miller

Research output: Contribution to journalArticle

247 Scopus citations

Abstract

Background: Interferon (IFN)-alpha has been used to study the effects of innate immune cytokines on the brain and behavior in humans. The degree to which peripheral administration of IFN-alpha accesses the brain and is associated with a central nervous system (CNS) inflammatory response is unknown. Moreover, the relationship among IFN-alpha-associated CNS inflammatory responses, neurotransmitter metabolism, and behavior has yet to be established. Methods: Twenty-four patients with hepatitis C underwent lumbar puncture and blood sampling after ∼12 weeks of either no treatment (n = 12) or treatment with pegylated IFN-alpha 2b (n = 12). Cerebrospinal fluid (CSF) and blood samples were analyzed for proinflammatory cytokines and their receptors as well as the chemokine, monocyte chemoattractant protein-1 (MCP-1), and IFN-alpha. Cerebrospinal fluid samples were additionally analyzed for monoamine metabolites and corticotropin releasing hormone. Depressive symptoms were assessed using the Montgomery Asberg Depression Rating Scale. Results: Interferon-alpha was detected in the CSF of all IFN-alpha-treated patients and only one control subject. Despite no increases in plasma IL-6, IFN-alpha-treated patients exhibited significant elevations in CSF IL-6 and MCP-1, both of which were highly correlated with CSF IFN-alpha concentrations. Of the immunologic and neurotransmitter variables, log-transformed CSF concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were the strongest predictor of depressive symptoms. Log-transformed CSF concentrations of IL-6, but not IFN-alpha or MCP-1, were negatively correlated with log-transformed CSF 5-HIAA (r2 = -.25, p < .05). Conclusions: These data indicate that a peripherally administered cytokine can activate a CNS inflammatory response in humans that interacts with monoamine (serotonin) metabolism, which is associated with depression.

Original languageEnglish (US)
Pages (from-to)296-303
Number of pages8
JournalBiological Psychiatry
Volume65
Issue number4
DOIs
StatePublished - Feb 15 2009

Keywords

  • Cerebrospinal fluid
  • cytokines
  • depression
  • inflammation
  • monoamines

ASJC Scopus subject areas

  • Biological Psychiatry

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    Raison, C. L., Borisov, A. S., Majer, M., Drake, D. F., Pagnoni, G., Woolwine, B. J., Vogt, G. J., Massung, B., & Miller, A. H. (2009). Activation of Central Nervous System Inflammatory Pathways by Interferon-Alpha: Relationship to Monoamines and Depression. Biological Psychiatry, 65(4), 296-303. https://doi.org/10.1016/j.biopsych.2008.08.010