title: Molecular signatures of peripheral blood mononuclear cells during chronic interferon-α treatment: relationship with depression and fatigue.
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.
  
  
  METHODS
  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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA. jfelger@gmail.com
authors.forename: J C
authors.initials: JC
authors.lastname: Felger
authors.forename: S W
authors.initials: SW
authors.lastname: Cole
authors.forename: T W W
authors.initials: TW
authors.lastname: Pace
authors.forename: F
authors.initials: F
authors.lastname: Hu
authors.forename: B J
authors.initials: BJ
authors.lastname: Woolwine
authors.forename: G H
authors.initials: GH
authors.lastname: Doho
authors.forename: C L
authors.initials: CL
authors.lastname: Raison
authors.forename: A H
authors.initials: AH
authors.lastname: Miller
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000187:drug effects / Q000235:genetics; D000998:Antiviral Agents / Q000009:adverse effects / Q000494:pharmacology*; D019295:Computational Biology / Q000379:methods; D003863:Depression / Q000139:chemically induced / Q000235:genetics*; D004359:Drug Therapy, Combination; D005221:Fatigue / Q000139:chemically induced / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods / Q000706:statistics & numerical data; D005786:Gene Expression Regulation / Q000187:drug effects; D019698:Hepatitis C, Chronic / Q000188:drug therapy; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000187:drug effects / Q000276:immunology*; D008137:Longitudinal Studies; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012254:Ribavirin / Q000627:therapeutic use; D012720:Severity of Illness Index
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D012333:RNA, Messenger; D012254:Ribavirin; D015088:2',5'-Oligoadenylate Synthetase