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

J. C. Felger, S. W. Cole, Thaddeus Wesley Warren Pace, F. Hu, B. J. Woolwine, G. H. Doho, Charles L Raison, A. H. Miller

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1591-1603
Number of pages13
JournalPsychological Medicine
Volume42
Issue number8
DOIs
StatePublished - Aug 2012
Externally publishedYes

Fingerprint

Interferon-alpha
Interferons
Fatigue
Blood Cells
Transcription Factors
Therapeutics
Genes
Chronic Fatigue Syndrome
Carrier Proteins
Transcription Factor AP-1
Ligases
Chronic Hepatitis C
Microarray Analysis
Computational Biology
Hepacivirus
Dendritic Cells
Communicable Diseases
Monocytes
Up-Regulation
Genome

Keywords

  • 2′-5′- oligoadenylate synthetase
  • Depression
  • fatigue
  • gene array
  • interferon-α

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Applied Psychology

Cite this

Molecular signatures of peripheral blood mononuclear cells during chronic interferon-α treatment : Relationship with depression and fatigue. / Felger, J. C.; Cole, S. W.; Pace, Thaddeus Wesley Warren; Hu, F.; Woolwine, B. J.; Doho, G. H.; Raison, Charles L; Miller, A. H.

In: Psychological Medicine, Vol. 42, No. 8, 08.2012, p. 1591-1603.

Research output: Contribution to journalArticle

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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.",
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AU - Cole, S. W.

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AU - Hu, F.

AU - Woolwine, B. J.

AU - Doho, G. H.

AU - Raison, Charles L

AU - Miller, A. H.

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