Psychological Medicine

Original Articles

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

J. C. Felgera1a2 c1, S. W. Colea3a4a5, T. W. W. Pacea1a2, F. Hua1a2, B. J. Woolwinea1a2, G. H. Dohoa6, C. L. Raisona1a2 and A. H. Millera1a2

a1 Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA

a2 The Winship Cancer Institute, Emory University, Atlanta, GA, USA

a3 Department of Medicine, Division of Hematology-Oncology, University of California, Los Angeles School of Medicine, Los Angeles, CA, USA

a4 Biology Institute and Jonsson Comprehensive Cancer Center, University of California, Los Angeles AIDS Institute, Los Angeles, CA, USA

a5 Cousins Center, University of California, Los Angeles, CA, USA

a6 Genomics Shared Resource, Emory University, Atlanta, GA, USA


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.

(Received August 05 2011)

(Revised November 07 2011)

(Accepted November 14 2011)

(Online publication December 09 2011)


c1 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: