Skip to main content
×
Home
    • Aa
    • Aa
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 21
  • Cited by
    This article has been cited by the following publications. This list is generated based on data provided by CrossRef.

    Bechter, Karl and Brown, David 2013. Neuroinflammation in psychiatric disorders – Evidence from research and clinic. Neurology, Psychiatry and Brain Research, Vol. 19, Issue. 4, p. 139.


    Malki, K Koritskaya, E Harris, F Bryson, K Herbster, M and Tosto, M G 2016. Epigenetic differences in monozygotic twins discordant for major depressive disorder. Translational Psychiatry, Vol. 6, Issue. 6, p. e839.


    Mills, Paul J. and Peterson, Christine T. 2016. Multiplexing and Beyond in Biobehavioral Research. Psychosomatic Medicine, Vol. 78, Issue. 6, p. 642.


    Cole, Steven W. 2013. Nervous system regulation of the cancer genome. Brain, Behavior, and Immunity, Vol. 30, p. S10.


    Felger, J.C. and Lotrich, F.E. 2013. Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications. Neuroscience, Vol. 246, p. 199.


    Neigh, Gretchen N. and Felger, Jennifer C. 2016. Editorial introduction: The effects of somatic disease and environmental insults on the stress response. Physiology & Behavior,


    Hepgul, Nilay Cattaneo, Annamaria Agarwal, Kosh Baraldi, Sara Borsini, Alessandra Bufalino, Chiara Forton, Daniel M Mondelli, Valeria Nikkheslat, Naghmeh Lopizzo, Nicola Riva, Marco A Russell, Alice Hotopf, Matthew and Pariante, Carmine M 2016. Transcriptomics in Interferon-α-Treated Patients Identifies Inflammation-, Neuroplasticity- and Oxidative Stress-Related Signatures as Predictors and Correlates of Depression. Neuropsychopharmacology, Vol. 41, Issue. 10, p. 2502.


    Borsini, A. and Zunszain, P. A. 2016. Stem Cells in Neuroendocrinology.


    Chou, Wen-Wen Huang, Chung-Feng Yeh, Ming-Lun Tsai, Yi-Shan Hsieh, Ming-Yen Huang, Ching-I Huang, Jee-Fu Tsai, Pei-Chien Hsi, Edward Juo, Suh-Hang Hank Tsai, Wei-Lun Chuang, Wan-Long Yu, Ming-Lung and Dai, Chia-Yen 2016. MicroRNA let-7g cooperates with interferon/ribavirin to repress hepatitis C virus replication. Journal of Molecular Medicine, Vol. 94, Issue. 3, p. 311.


    Nunes, Eric J. Randall, Patrick A. Estrada, Alexavier Epling, Brian Hart, Evan E. Lee, Christie A. Baqi, Younis Müller, Christa E. Correa, Mercè and Salamone, John D. 2014. Effort-related motivational effects of the pro-inflammatory cytokine interleukin 1-beta: studies with the concurrent fixed ratio 5/ chow feeding choice task. Psychopharmacology, Vol. 231, Issue. 4, p. 727.


    Miaskowski, Christine Cooper, Bruce A. Melisko, Michelle Chen, Lee-May Mastick, Judy West, Claudia Paul, Steven M. Dunn, Laura B. Schmidt, Brian L. Hammer, Marilyn Cartwright, Frances Wright, Fay Langford, Dale J. Lee, Kathryn and Aouizerat, Bradley E. 2014. Disease and treatment characteristics do not predict symptom occurrence profiles in oncology outpatients receiving chemotherapy. Cancer, Vol. 120, Issue. 15, p. 2371.


    Yohn, Samantha E. Arif, Yumna Haley, Allison Tripodi, Guiseppe Baqi, Younis Müller, Christa E. Miguel, Noemi San Correa, Mercè and Salamone, John D. 2016. Effort-related motivational effects of the pro-inflammatory cytokine interleukin-6: pharmacological and neurochemical characterization. Psychopharmacology, Vol. 233, Issue. 19-20, p. 3575.


    Gerber, Lynn Estep, Michael Stepanova, Maria Escheik, Carey Weinstein, Ali and Younossi, Zobair M. 2016. Effects of Viral Eradication With Ledipasvir and Sofosbuvir, With or Without Ribavirin, on Measures of Fatigue in Patients With Chronic Hepatitis C Virus Infection. Clinical Gastroenterology and Hepatology, Vol. 14, Issue. 1, p. 156.


    Sekio, M. and Seki, K. 2015. Lipopolysaccharide-Induced Depressive-Like Behavior is Associated with  1-Adrenoceptor Dependent Downregulation of the Membrane GluR1 Subunit in the Mouse Medial Prefrontal Cortex and Ventral Tegmental Area. International Journal of Neuropsychopharmacology, Vol. 18, Issue. 1, p. pyu005.


    Rawdin, B.J. Mellon, S.H. Dhabhar, F.S. Epel, E.S. Puterman, E. Su, Y. Burke, H.M. Reus, V.I. Rosser, R. Hamilton, S.P. Nelson, J.C. and Wolkowitz, O.M. 2013. Dysregulated relationship of inflammation and oxidative stress in major depression. Brain, Behavior, and Immunity, Vol. 31, p. 143.


    Felger, Jennifer C. Haroon, Ebrahim Woolwine, Bobbi J. Raison, Charles L. and Miller, Andrew H. 2015. Interferon-alpha-induced inflammation is associated with reduced glucocorticoid negative feedback sensitivity and depression in patients with hepatitis C virus. Physiology & Behavior,


    Modabbernia, Amirhossein Poustchi, Hossein and Malekzadeh, Reza 2013. Neuropsychiatric and Psychosocial Issues of Patients With Hepatitis C Infection: A Selective Literature Review. Hepatitis Monthly, Vol. 13, Issue. 1,


    Mellon, S H Wolkowitz, O M Schonemann, M D Epel, E S Rosser, R Burke, H B Mahan, L Reus, V I Stamatiou, D Liew, C -C and Cole, S W 2016. Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment. Translational Psychiatry, Vol. 6, Issue. 5, p. e821.


    Light, Kathleen C. Agarwal, Neeraj Iacob, Eli White, Andrea T. Kinney, Anita Y. VanHaitsma, Timothy A. Aizad, Hannah Hughen, Ronald W. Bateman, Lucinda and Light, Alan R. 2013. Differing leukocyte gene expression profiles associated with fatigue in patients with prostate cancer versus chronic fatigue syndrome. Psychoneuroendocrinology, Vol. 38, Issue. 12, p. 2983.


    Felger, Jennifer C. Li, Li Marvar, Paul J. Woolwine, Bobbi J. Harrison, David G. Raison, Charles L. and Miller, Andrew H. 2013. Tyrosine metabolism during interferon-alpha administration: Association with fatigue and CSF dopamine concentrations. Brain, Behavior, and Immunity, Vol. 31, p. 153.


    ×

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

  • J. C. Felger (a1) (a2), S. W. Cole (a3) (a4) (a5), T. W. W. Pace (a1) (a2), F. Hu (a1) (a2), B. J. Woolwine (a1) (a2), G. H. Doho (a6), C. L. Raison (a1) (a2) and A. H. Miller (a1) (a2)
  • DOI: http://dx.doi.org/10.1017/S0033291711002868
  • Published online: 09 December 2011
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.

Copyright
Corresponding author
*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: jfelger@gmail.com)
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

JA Blendy (2006). The role of CREB in depression and antidepressant treatment. Biological Psychiatry 59, 11441150.

BMBolstad , RAIrizarry , MAstrand , TPSpeed (2003). A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19, 185193.

JEBower , PAGanz , NAziz , JLFahey (2002). Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosomatic Medicine 64, 604611.

JEBower , PAGanz , MRIrwin , JMArevalo , SWCole (2011). Fatigue and gene expression in human leukocytes: increased NF-kappaB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue. Brain, Behavior, and Immunity 25, 147150.

GChen , KAHasanat , JMBebchuk , GJMoore , DGlitz , HKManji (1999). Regulation of signal transduction pathways and gene expression by mood stabilizers and antidepressants. Psychosomatic Medicine 61, 599617.

SWCole , ZGalic , JAZack (2003). Controlling false-negative errors in microarray differential expression analysis: a PRIM approach. Bioinformatics 19, 18081816.

SW Cole , LC Hawkley , JM Arevalo , JT Cacioppo (2011). Transcript origin analysis identifies antigen-presenting cells as primary targets of socially regulated gene expression in leukocytes. Proceedings of the National Academy of Science USA 108, 30803085.

SW Cole , W Yan , Z Galic , J Arevalo , JA Zack (2005). Expression-based monitoring of transcription factor activity: the TELiS database. Bioinformatics 21, 803810.

JEDarnellJr. , IMKerr , GRStark (1994). Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 14151421.

DLEvans , DSCharney , LLewis , RNGolden , JMGorman , KRKrishnan , CBNemeroff , JDBremner , RMCarney , JCCoyne , MRDelong , NFrasure-Smith , AHGlassman , PWGold , IGrant , LGwyther , GIronson , RLJohnson , AMKanner , WJKaton , PGKaufmann , FJKeefe , TKetter , TPLaughren , JLeserman , CGLyketsos , WMMcDonald , BSMcEwen , AHMiller , DMusselman , CO'Connor , JMPetitto , BGPollock , RGRobinson , SPRoose , JRowland , YSheline , DSSheps , GSimon , DSpiegel , AStunkard , TSunderland , PTibbitsJr. , WJValvo (2005). Mood disorders in the medically ill: scientific review and recommendations. Biological Psychiatry 58, 175189.

DL Evans , JD Folds , JM Petitto , RN Golden , CA Pedersen , M Corrigan , JH Gilmore , SG Silva , D Quade , H Ozer (1992). Circulating natural killer cell phenotypes in men and women with major depression. Relation to cytotoxic activity and severity of depression. Archives of General Psychiatry 49, 388395.

JCFelger , OAlagbe , TWPace , BJWoolwine , FHu , CLRaison , AHMiller (2011). Early activation of p38 mitogen activated protein kinase is associated with interferon-alpha-induced depression and fatigue. Brain, Behavior, and Immunity 25, 10941098.

MF Folstein , SE Folstein , PR McHugh (1975). ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 12, 189198.

JEGottenberg , NCagnard , CLucchesi , FLetourneur , SMistou , TLazure , SJacques , NBa , MIttah , CLepajolec , MLabetoulle , MArdizzone , JSibilia , CFournier , GChiocchia , XMariette (2006). Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjogren's syndrome. Proceedings of the National Academy of Science USA 103, 27702775.

MIrwin , TPatterson , TLSmith , CCaldwell , SABrown , JCGillin , IGrant (1990). Reduction of immune function in life stress and depression. Biological Psychiatry 27, 2230.

NPKearns , CACruickshank , KJMcGuigan , SARiley , SPShaw , RPSnaith (1982). A comparison of depression rating scales. British Journal of Psychiatry 141, 4549.

NG Klimas , AO Koneru (2007). Chronic fatigue syndrome: inflammation, immune function, and neuroendocrine interactions. Current Rheumatology Reports 9, 482487.

JMKoch , SKell , DHinze-Selch , JBAldenhoff (2002). Changes in CREB-phosphorylation during recovery from major depression. Journal of Psychiatric Research 36, 369375.

M Kojima , T Kojima , S Suzuki , T Oguchi , M Oba , H Tsuchiya , F Sugiura , Y Kanayama , TA Furukawa , S Tokudome , N Ishiguro (2009). Depression, inflammation, and pain in patients with rheumatoid arthritis. Arthritis and Rheumatism 61, 10181024.

EKozora , MCEllison , SWest (2006). Depression, fatigue, and pain in systemic lupus erythematosus (SLE): relationship to the American College of Rheumatology SLE neuropsychological battery. Arthritis and Rheumatism 55, 628635.

KKrishnaraju , HQNguyen , DALiebermann , BHoffman (1995). The zinc finger transcription factor Egr-1 potentiates macrophage differentiation of hematopoietic cells. Molecular and Cellular Biology 15, 54995507.

SDKuipers , ATrentani , CWestenbroek , CRBramham , JKorf , IPKema , GJTer Horst , JADen Boer (2006). Unique patterns of FOS, phospho-CREB and BrdU immunoreactivity in the female rat brain following chronic stress and citalopram treatment. Neuropharmacology 50, 428440.

ICLai , CJHong , SJTsai (2003). Expression of cAMP response element-binding protein in major depression before and after antidepressant treatment. Neuropsychobiology 48, 182185.

SKLutgendorf , KDeGeest , CYSung , JMArevalo , FPenedo , JLucci3rd , MGoodheart , DLubaroff , DMFarley , ASood , SWCole (2009). Depression, social support, and beta-adrenergic transcription control in human ovarian cancer. Brain, Behavior, and Immunity 23, 176183.

C Maddock , A Baita , MG Orru , R Sitzia , A Costa , E Muntoni , MG Farci , B Carpiniello , CM Pariante (2004). Psychopharmacological treatment of depression, anxiety, irritability and insomnia in patients receiving interferon-alpha: a prospective case series and a discussion of biological mechanisms. Journal of Psychopharmacology 18, 4146.

MMajer , LAWelberg , LCapuron , GPagnoni , CLRaison , AHMiller (2008). IFN-alpha-induced motor slowing is associated with increased depression and fatigue in patients with chronic hepatitis C. Brain, Behavior, and Immunity 22, 870880.

JAMerritt , ECBorden , LABall (1985). Measurement of 2′,5′-oligoadenylate synthetase in patients receiving interferon-alpha. Journal of Interferon Research 5, 191198.

AHMiller (2009). Norman Cousins Lecture. Mechanisms of cytokine-induced behavioral changes: psychoneuroimmunology at the translational interface. Brain, Behavior, and Immunity 23, 149158.

GEMiller , EChen , JSze , TMarin , JMArevalo , RDoll , RMa , SWCole (2008). A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-kappaB signaling. Biological Psychiatry 64, 266272.

AMoeenrezakhanlou , LShephard , LLam , NEReiner (2008). Myeloid cell differentiation in response to calcitriol for expression CD11b and CD14 is regulated by myeloid zinc finger-1 protein downstream of phosphatidylinositol 3-kinase. Journal of Leukocyte Biology 84, 519528.

SA Montgomery , M Asberg (1979). A new depression scale designed to be sensitive to change. Brtish Journal of Psychiatry 134, 382389.

S Morinobu , M Nibuya , RS Duman (1995). Chronic antidepressant treatment down-regulates the induction of c-fos mRNA in response to acute stress in rat frontal cortex. Neuropsychopharmacology 12, 221228.

DLMusselman , DHLawson , JFGumnick , AKManatunga , SPenna , RSGoodkin , KGreiner , CBNemeroff , AHMiller (2001). Paroxetine for the prevention of depression induced by high-dose interferon alfa. New England Journal of Medicine 344, 961966.

WFNg , SJBowman (2010). Primary Sjögren's syndrome: too dry and too tired. Rheumatology (Oxford) 49, 844853.

CM Pariante , AH Miller (1995). Natural killer cell activity in major depression: a prospective study of the in vivo effects of desmethylimipramine treatment. European Neuropsychopharmacology 5 (Suppl.), 8388.

GG Potter , JD Kittinger , HR Wagner , DC Steffens , KR Krishnan (2004). Prefrontal neuropsychological predictors of treatment remission in late-life depression. Neuropsychopharmacology 29, 22662271.

CLRaison , ASBorisov , MMajer , DFDrake , GPagnoni , BJWoolwine , GJVogt , BMassung , AHMiller (2009 a). Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression. Biological Psychiatry 65, 296303.

CL Raison , AS Borisov , BJ Woolwine , B Massung , G Vogt , AH Miller (2010 a). Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior. Molecular Psychiatry 15, 535547.

CLRaison , LCapuron , AHMiller (2006). Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends in Immunology 27, 2431.

CL Raison , R Dantzer , KW Kelley , MA Lawson , BJ Woolwine , G Vogt , JR Spivey , K Saito , AH Miller (2010 b). CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Molecular Psychiatry 15, 393403.

CL Raison , M Demetrashvili , L Capuron , AH Miller (2005). Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs 19, 105123.

CLRaison , JMLin , WCReeves (2009 b). Association of peripheral inflammatory markers with chronic fatigue in a population-based sample. Brain, Behavior, and Immunity 23, 327337.

WC Reeves , D Wagner , R Nisenbaum , JF Jones , B Gurbaxani , L Solomon , DA Papanicolaou , ER Unger , SD Vernon , C Heim (2005). Chronic fatigue syndrome – a clinically empirical approach to its definition and study. BMC Medicine 3, 19.

LRonnblom , MLEloranta , GVAlm (2003). Role of natural interferon-alpha producing cells (plasmacytoid dendritic cells) in autoimmunity. Autoimmunity 36, 463472.

S Saha , PN Rangarajan (2003). Common host genes are activated in mouse brain by Japanese encephalitis and rabies viruses. Journal of General Virology 84, 17291735.

VM Sanders , RH Straub (2002). Norepinephrine, the beta-adrenergic receptor, and immunity. Brain, Behavior, and Immunity 16, 290332.

EM Smets , B Garssen , B Bonke , JC De Haes (1995). The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. Journal of Psychosomatic Research 39, 315325.

RJSuhadolnik , NLReichenbach , PHitzges , RWSobol , DLPeterson , BHenry , DVAblashi , WEMuller , HCSchroder , WACarter , DRStrayer (1994 b). Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome. Clinical Infectious Diseases 18 (Suppl. 1), S96–S104.

MW Taylor , WM Grosse , JE Schaley , C Sanda , X Wu , SC Chien , F Smith , TG Wu , M Stephens , MW Ferris , JN McClintick , RE Jerome , HJ Edenberg (2004). Global effect of PEG-IFN-alpha and ribavirin on gene expression in PBMC in vitro. Journal of Interferon and Cytokine Research 24, 107118.

VG Tusher , R Tibshirani , G Chu (2001). Significance analysis of microarrays applied to the ionizing radiation response. Proceedings of the National Academy of Science USA 98, 51165121.

AVojdani , MGhoneum , PCChoppa , LMagtoto , CWLapp (1997). Elevated apoptotic cell population in patients with chronic fatigue syndrome: the pivotal role of protein kinase RNA. Journal of Internal Medicine 242, 465478.

AVojdani , CWLapp (1999). Interferon-induced proteins are elevated in blood samples of patients with chemically or virally induced chronic fatigue syndrome. Immunopharmacology and Immunotoxicology 21, 175202.

TLWallace , KEStellitano , RLNeve , RSDuman (2004). Effects of cyclic adenosine monophosphate response element binding protein overexpression in the basolateral amygdala on behavioral models of depression and anxiety. Biological Psychiatry 56, 151160.

JWang , ILCampbell , HZhang (2008). Systemic interferon-alpha regulates interferon-stimulated genes in the central nervous system. Molecular Psychiatry 13, 293301.

J Wang , AJ Dunn , AJ Roberts , H Zhang (2009). Decreased immobility in swimming test by homologous interferon-alpha in mice accompanied with increased cerebral tryptophan level and serotonin turnover. Neuroscience Letters 452, 96–100.


S Yamada , M Yamamoto , H Ozawa , P Riederer , T Saito (2003). Reduced phosphorylation of cyclic AMP-responsive element binding protein in the postmortem orbitofrontal cortex of patients with major depressive disorder. Journal of Neural Transmission 110, 671680.

RYirmiya , YPollak , MMorag , AReichenberg , OBarak , RAvitsur , YShavit , HOvadia , JWeidenfeld , AMorag , MENewman , TPollmächer (2000). Illness, cytokines, and depression. Annals of the New York Academy of Sciences 917, 478487.

TZarubin , JHan (2005). Activation and signaling of the p38 MAP kinase pathway. Cell Research 15, 1118.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords: