Activation of CNS 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 ~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 (MCP)-1, and IFN-alpha. CSF samples were additionally analyzed for monoamine metabolites and corticotropin releasing hormone. Depressive symptoms were assessed using the Montgomery Asberg Depression Rating Scale. Results—IFN-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=−0.25, p<0.05). 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. Corresponding Author: Andrew H. Miller, M.D., Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Rd, 5th floor, Atlanta, GA 30322, Phone 404-727-8260, FAX 404-778-5550, email amill02@emory.edu. Financial Disclosures Charles L. Raison is on the speakers’ bureau for Lilly and Wyeth and Schering-Plough and has served as a consultant or an advisory board member for Schering-Plough, Wyeth, Lilly, and Centocor; Andrey S. Borisov, Matthias Majer, Daniel F. Drake, Giuseppe Pagnoni, Bobbi J Woolwine, Gerald Vogt, and Breanne Massung reported no biomedical financial interests or potential conflicts of interests; Andrew H. Miller has served as a consultant or an advisory board member for Schering-Plough and Centocor, and has received research funding from Janssen/Johnson and Johnson, GlaxoSmithKline, and Schering-Plough. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author Manuscript Biol Psychiatry. Author manuscript; available in PMC 2010 February 15. Published in final edited form as: Biol Psychiatry. 2009 February 15; 65(4): 296–303. doi:10.1016/j.biopsych. 2008.08. 010. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript