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

• Authors: Jennifer Felger, Emory University; Steve W. Cole, University of California, Los Angeles; Thaddeus Pace, Emory University; Fang Hu, Emory University; Bobbi J. Woolwine, Emory University; Gregory H. Doho, Emory University; Charles Raison, Emory University; Andrew H Miller, Emory University
• Journal Title: Psychological Medicine
• Volume: Volume 42, Number 8
• Publisher: Cambridge University Press (CUP): STM Journals | 2012-08-01, Pages 1591-1603
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1017/S0033291711002868
• Subjects: Psychology, Clinical; Health Sciences, Oncology; Biology, Genetics
• Keywords: Social Sciences; Science & Technology; Life Sciences & Biomedicine; Psychology, Clinical; Psychiatry; Psychology; Depression; fatigue; gene array; interferon-alpha; 2 '-5 '-oligoadenylate synthetase; SIGNAL-TRANSDUCTION PATHWAYS; ELEMENT-BINDING PROTEIN; CENTRAL-NERVOUS-SYSTEM; PRIMARY SJOGRENS-SYNDROME; L ANTIVIRAL PATHWAY; IFN-ALPHA; MAJOR DEPRESSION; GENE-EXPRESSION; ANTIDEPRESSANT TREATMENT; CHRONIC STRESS

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.