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

  • J. C. Felger (a1) (a2), S. W. Cole (a3) (a4) (a5), T. W. W. Pace (a1) (a2), F. Hu (a1) (a2), B. J. Woolwine (a1) (a2), G. H. Doho (a6), C. L. Raison (a1) (a2) and A. H. Miller (a1) (a2)...
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.

Copyright
Corresponding author
*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: jfelger@gmail.com)
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Supplementary Tables

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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Supplementary Tables

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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Supplementary Tables

Felger Supplementary Material
Felger Supplementary Material

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Supplementary Tables

Felger Supplementary Table 2
Supplementary Table S2. Ingenuity canonical pathways analysis of genes differentially regulated by IFN-alpha.

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