Psychol Med. 2011 Dec 9:1-13. [Epub ahead of print]
Molecular signatures of peripheral blood mononuclear cells during
chronic interferon-=E1 treatment: relationship with depression and
fatigue.
Felger JC, Cole SW, Pace TW, Hu F, Woolwine BJ, Doho GH, Raison CL, Miller =
AH.
SourceDepartment of Psychiatry and Behavioral Sciences, Emory
University, Atlanta, GA, USA.
Abstract
BACKGROUND: Interferon-alpha (IFN-=E1) 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-=E1 on immune cells in vivo and its relationship to
IFN-=E1-induced behavioral changes.MethodGenome-wide transcriptional
profiling was performed on peripheral blood mononuclear cells (PBMCs)
from 21 patients with chronic hepatitis C virus (HCV) either awaiting
IFN-=E1 therapy (n=3D10) or at 12 weeks of IFN-=E1 treatment (n=3D11).
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-=E1-induced
depression/fatigue, and correlated with depression and fatigue scores
at 12 weeks (r=3D0.80, p=3D0.003 and r=3D0.70, p=3D0.017 respectively).
Promoter-based bioinformatic analyses linked IFN-=E1-related
transcriptional alterations to transcription factors involved in
myeloid differentiation, IFN-=E1 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-=E1-treated patients
with high depression/fatigue scores demonstrated up-regulation of
genes bearing promoter motifs for transcription factors involved in
myeloid differentiation, IFN-=E1 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-=E1
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.
PMID:22152193[PubMed - as supplied by publisher]
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