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

233 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Interferon-alpha
Cerebrospinal Fluid
Central Nervous System
Depression
Chemokine CCL2
Interleukin-6
Hydroxyindoleacetic Acid
Neurotransmitter Agents
Serotonin
Cytokines
Cytokine Receptors
Spinal Puncture
Corticotropin-Releasing Hormone
Brain
Hepatitis C
Chemokines
Therapeutics

Keywords

  • Cerebrospinal fluid
  • cytokines
  • depression
  • inflammation
  • monoamines

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Activation of Central Nervous System Inflammatory Pathways by Interferon-Alpha : Relationship to Monoamines and Depression. / Raison, Charles L; Borisov, Andrey S.; Majer, Matthias; Drake, Daniel F.; Pagnoni, Giuseppe; Woolwine, Bobbi J.; Vogt, Gerald J.; Massung, Breanne; Miller, Andrew H.

In: Biological Psychiatry, Vol. 65, No. 4, 15.02.2009, p. 296-303.

Research output: Contribution to journalArticle

Raison, CL, Borisov, AS, Majer, M, Drake, DF, Pagnoni, G, Woolwine, BJ, Vogt, GJ, Massung, B & Miller, AH 2009, 'Activation of Central Nervous System Inflammatory Pathways by Interferon-Alpha: Relationship to Monoamines and Depression', Biological Psychiatry, vol. 65, no. 4, pp. 296-303. https://doi.org/10.1016/j.biopsych.2008.08.010
Raison, Charles L ; Borisov, Andrey S. ; Majer, Matthias ; Drake, Daniel F. ; Pagnoni, Giuseppe ; Woolwine, Bobbi J. ; Vogt, Gerald J. ; Massung, Breanne ; Miller, Andrew H. / Activation of Central Nervous System Inflammatory Pathways by Interferon-Alpha : Relationship to Monoamines and Depression. In: Biological Psychiatry. 2009 ; Vol. 65, No. 4. pp. 296-303.
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AU - Raison, Charles L

AU - Borisov, Andrey S.

AU - Majer, Matthias

AU - Drake, Daniel F.

AU - Pagnoni, Giuseppe

AU - Woolwine, Bobbi J.

AU - Vogt, Gerald J.

AU - Massung, Breanne

AU - Miller, Andrew H.

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