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Molecular signatures of peripheral blood mononuclear cells during chronic interferon-α treatment: relationship with depression and fatigue

Published online by Cambridge University Press:  09 December 2011

J. C. Felger ,
S. W. Cole ,
T. W. W. Pace ,
F. Hu ,
B. J. Woolwine ,
G. H. Doho ,
C. L. Raison  and
A. H. Miller
J. C. Felger*
Affiliation:
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA The Winship Cancer Institute, Emory University, Atlanta, GA, USA
S. W. Cole
Affiliation:
Department of Medicine, Division of Hematology-Oncology, University of California, Los Angeles School of Medicine, Los Angeles, CA, USA Biology Institute and Jonsson Comprehensive Cancer Center, University of California, Los Angeles AIDS Institute, Los Angeles, CA, USA Cousins Center, University of California, Los Angeles, CA, USA
T. W. W. Pace
Affiliation:
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA The Winship Cancer Institute, Emory University, Atlanta, GA, USA
F. Hu
Affiliation:
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA The Winship Cancer Institute, Emory University, Atlanta, GA, USA
B. J. Woolwine
Affiliation:
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA The Winship Cancer Institute, Emory University, Atlanta, GA, USA
G. H. Doho
Affiliation:
Genomics Shared Resource, Emory University, Atlanta, GA, USA
C. L. Raison
Affiliation:
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA The Winship Cancer Institute, Emory University, Atlanta, GA, USA
A. H. Miller
Affiliation:
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA The Winship Cancer Institute, Emory University, Atlanta, GA, USA
*
*Address for correspondence: J. C. Felger, Ph.D., Winship Cancer Institute, Emory University School of Medicine, 1365-B Clifton Road, 5th Floor, Atlanta, GA 30322, USA. (Email: [email protected])
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Abstract

Background

Interferon-alpha (IFN-α) treatment for infectious disease and cancer causes high rates of depression and fatigue, and has been used to investigate the impact of inflammatory cytokines on brain and behavior. However, little is known about the transcriptional impact of chronic IFN-α on immune cells in vivo and its relationship to IFN-α-induced behavioral changes.

Method

Genome-wide transcriptional profiling was performed on peripheral blood mononuclear cells (PBMCs) from 21 patients with chronic hepatitis C virus (HCV) either awaiting IFN-α therapy (n=10) or at 12 weeks of IFN-α treatment (n=11).

Results

Significance analysis of microarray data identified 252 up-regulated and 116 down-regulated gene transcripts. Of the up-regulated genes, 2′-5′-oligoadenylate synthetase 2 (OAS2), a gene linked to chronic fatigue syndrome (CFS), was the only gene that was differentially expressed in patients with IFN-α-induced depression/fatigue, and correlated with depression and fatigue scores at 12 weeks (r=0.80, p=0.003 and r=0.70, p=0.017 respectively). Promoter-based bioinformatic analyses linked IFN-α-related transcriptional alterations to transcription factors involved in myeloid differentiation, IFN-α signaling, activator protein-1 (AP1) and cAMP responsive element binding protein/activation transcription factor (CREB/ATF) pathways, which were derived primarily from monocytes and plasmacytoid dendritic cells. IFN-α-treated patients with high depression/fatigue scores demonstrated up-regulation of genes bearing promoter motifs for transcription factors involved in myeloid differentiation, IFN-α and AP1 signaling, and reduced prevalence of motifs for CREB/ATF, which has been implicated in major depression.

Conclusions

Depression and fatigue during chronic IFN-α administration were associated with alterations in the expression (OAS2) and transcriptional control (CREB/ATF) of genes linked to behavioral disorders including CFS and major depression, further supporting an immune contribution to these diseases.

Keywords

Depressionfatiguegene arrayinterferon-α2′-5′-oligoadenylate synthetase
Type
Original Articles
Information
Psychological Medicine , Volume 42 , Issue 8 , August 2012 , pp. 1591 - 1603
Copyright
Copyright © Cambridge University Press 2011

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Supplementary material: File

Felger Supplementary Table 1

Supplementary Table S1. Gene transcripts significantly up- and down-regulated in subjects administered 12 weeks IFN-alpha and ribavirin (n=11) compared to controls (n=10) as identified by SAM.

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Felger Supplementary Table 2

Supplementary Table S2. Ingenuity canonical pathways analysis of genes differentially regulated by IFN-alpha.

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Felger Supplementary Table 3

Supplementary Table S3. Gene transcripts up- and down-regulated by 50% (≥1.5 fold) in IFN-alpha-treated subjects (n=11) compared to control (n=10), and in subjects with high (n=4) versus low (n=7) MADRS and MFI scores at 12 weeks IFN-alpha.

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Felger Supplementary Material

Felger Supplementary Material

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