Molecular signatures of peripheral blood mononuclear cells during chronic interferon-α treatment: relationship with depression and fatigue.
Title | Molecular signatures of peripheral blood mononuclear cells during chronic interferon-α treatment: relationship with depression and fatigue. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Felger JC, Cole SW, Pace TWW, Hu F, Woolwine BJ, Doho GH, Raison CL, Miller AH |
Journal | Psychol Med |
Volume | 42 |
Issue | 8 |
Pagination | 1591-603 |
Date Published | 2012 Aug |
ISSN | 1469-8978 |
Keywords | 2',5'-Oligoadenylate Synthetase, Antiviral Agents, Computational Biology, Depression, Drug Therapy, Combination, Fatigue, Female, Gene Expression Profiling, Gene Expression Regulation, Hepatitis C, Chronic, Humans, Interferon-alpha, Leukocytes, Mononuclear, Longitudinal Studies, Male, Microarray Analysis, Middle Aged, Promoter Regions, Genetic, Reverse Transcriptase Polymerase Chain Reaction, Ribavirin, RNA, Messenger, Severity of Illness Index |
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. |
DOI | 10.1017/S0033291711002868 |
Alternate Journal | Psychol Med |
PubMed ID | 22152193 |
PubMed Central ID | PMC3433045 |
Grant List | F32 MH093054 / MH / NIMH NIH HHS / United States F32 MH093054 / MH / NIMH NIH HHS / United States K05 MH069124 / MH / NIMH NIH HHS / United States K05 MH069124 / MH / NIMH NIH HHS / United States K23 MH064619 / MH / NIMH NIH HHS / United States K23 MH064619 / MH / NIMH NIH HHS / United States M01 RR0039 / RR / NCRR NIH HHS / United States P30 AI050409 / AI / NIAID NIH HHS / United States R01 AT004698 / AT / NCCIH NIH HHS / United States R01 AT007297 / AT / NCCIH NIH HHS / United States R01 HL073921 / HL / NHLBI NIH HHS / United States R01 HL073921 / HL / NHLBI NIH HHS / United States R01 MH070553 / MH / NIMH NIH HHS / United States R01 MH070553 / MH / NIMH NIH HHS / United States R01 MH075102 / MH / NIMH NIH HHS / United States R01 MH087604 / MH / NIMH NIH HHS / United States R01MH075102 / MH / NIMH NIH HHS / United States T32 MH020018 / MH / NIMH NIH HHS / United States T32 MH020018 / MH / NIMH NIH HHS / United States UL1 RR025008 / RR / NCRR NIH HHS / United States UL1 RR025008 / RR / NCRR NIH HHS / United States UL1 TR000454 / TR / NCATS NIH HHS / United States |