Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression.
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 approximately 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 (r(2) = -.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.
Raison
Charles L
CL
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA.
Borisov
Andrey S
AS
Majer
Matthias
M
Drake
Daniel F
DF
Pagnoni
Giuseppe
G
Woolwine
Bobbi J
BJ
Vogt
Gerald J
GJ
Massung
Breanne
B
Miller
Andrew H
AH
D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000134:cerebrospinal fluid / Q000502:physiology*; D015415:Biomarkers / Q000032:analysis; D002490:Central Nervous System / Q000187:drug effects* / Q000473:pathology*; D003346:Corticotropin-Releasing Hormone / Q000134:cerebrospinal fluid; D016207:Cytokines / Q000134:cerebrospinal fluid; D003866:Depressive Disorder / Q000134:cerebrospinal fluid / Q000473:pathology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000134:cerebrospinal fluid / Q000473:pathology*; D016898:Interferon-alpha / Q000494:pharmacology*; D008137:Longitudinal Studies; D008297:Male; D009434:Neural Pathways / Q000187:drug effects* / Q000473:pathology*; D011569:Psychiatric Status Rating Scales; D012254:Ribavirin / Q000494:pharmacology
D000998:Antiviral Agents; D015306:Biogenic Monoamines; D015415:Biomarkers; D016207:Cytokines; D016898:Interferon-alpha; D012254:Ribavirin; D003346:Corticotropin-Releasing Hormone
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