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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)...



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.


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).


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.


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.


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:


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Akwa, Y, Hassett, DE, Eloranta, ML, Sandberg, K, Masliah, E, Powell, H, Whitton, JL, Bloom, FE, Campbell, IL (1998). Transgenic expression of IFN-alpha in the central nervous system of mice protects against lethal neurotropic viral infection but induces inflammation and neurodegeneration. Journal of Immunology 161, 50165026.
Blendy, JA (2006). The role of CREB in depression and antidepressant treatment. Biological Psychiatry 59, 11441150.
Bolstad, BM, Irizarry, RA, Astrand, M, Speed, TP (2003). A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19, 185193.
Bower, JE, Ganz, PA, Aziz, N, Fahey, JL (2002). Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosomatic Medicine 64, 604611.
Bower, JE, Ganz, PA, Irwin, MR, Arevalo, JM, Cole, SW (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.
Chen, G, Hasanat, KA, Bebchuk, JM, Moore, GJ, Glitz, D, Manji, HK (1999). Regulation of signal transduction pathways and gene expression by mood stabilizers and antidepressants. Psychosomatic Medicine 61, 599617.
Cole, SW, Galic, Z, Zack, JA (2003). Controlling false-negative errors in microarray differential expression analysis: a PRIM approach. Bioinformatics 19, 18081816.
Cole, SW, Hawkley, LC, Arevalo, JM, Cacioppo, JT (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.
Cole, SW, Yan, W, Galic, Z, Arevalo, J, Zack, JA (2005). Expression-based monitoring of transcription factor activity: the TELiS database. Bioinformatics 21, 803810.
Darnell, JE Jr., Kerr, IM, Stark, GR (1994). Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 14151421.
Evans, DL, Charney, DS, Lewis, L, Golden, RN, Gorman, JM, Krishnan, KR, Nemeroff, CB, Bremner, JD, Carney, RM, Coyne, JC, Delong, MR, Frasure-Smith, N, Glassman, AH, Gold, PW, Grant, I, Gwyther, L, Ironson, G, Johnson, RL, Kanner, AM, Katon, WJ, Kaufmann, PG, Keefe, FJ, Ketter, T, Laughren, TP, Leserman, J, Lyketsos, CG, McDonald, WM, McEwen, BS, Miller, AH, Musselman, D, O'Connor, C, Petitto, JM, Pollock, BG, Robinson, RG, Roose, SP, Rowland, J, Sheline, Y, Sheps, DS, Simon, G, Spiegel, D, Stunkard, A, Sunderland, T, Tibbits, P Jr., Valvo, WJ (2005). Mood disorders in the medically ill: scientific review and recommendations. Biological Psychiatry 58, 175189.
Evans, DL, Folds, JD, Petitto, JM, Golden, RN, Pedersen, CA, Corrigan, M, Gilmore, JH, Silva, SG, Quade, D, Ozer, H (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.
Felger, JC, Alagbe, O, Pace, TW, Woolwine, BJ, Hu, F, Raison, CL, Miller, AH (2011). Early activation of p38 mitogen activated protein kinase is associated with interferon-alpha-induced depression and fatigue. Brain, Behavior, and Immunity 25, 10941098.
First, MB, Spitzer, RL, Gibbon, M, Williams, JB (1997). Structured Clinical Interview for DSM-IV. American Psychiatric Press: Washington, DC.
Folstein, MF, Folstein, SE, McHugh, PR (1975). ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 12, 189198.
Gottenberg, JE, Cagnard, N, Lucchesi, C, Letourneur, F, Mistou, S, Lazure, T, Jacques, S, Ba, N, Ittah, M, Lepajolec, C, Labetoulle, M, Ardizzone, M, Sibilia, J, Fournier, C, Chiocchia, G, Mariette, X (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.
Haque, SJ, Williams, BR (1998). Signal transduction in the interferon system. Seminars in Oncology 25, 1422.
Irwin, M, Patterson, T, Smith, TL, Caldwell, C, Brown, SA, Gillin, JC, Grant, I (1990). Reduction of immune function in life stress and depression. Biological Psychiatry 27, 2230.
Kearns, NP, Cruickshank, CA, McGuigan, KJ, Riley, SA, Shaw, SP, Snaith, RP (1982). A comparison of depression rating scales. British Journal of Psychiatry 141, 4549.
Klimas, NG, Koneru, AO (2007). Chronic fatigue syndrome: inflammation, immune function, and neuroendocrine interactions. Current Rheumatology Reports 9, 482487.
Klimas, NG, Salvato, FR, Morgan, R, Fletcher, MA (1990). Immunologic abnormalities in chronic fatigue syndrome. Journal of Clinical Microbiology 28, 14031410.
Koch, JM, Kell, S, Hinze-Selch, D, Aldenhoff, JB (2002). Changes in CREB-phosphorylation during recovery from major depression. Journal of Psychiatric Research 36, 369375.
Kojima, M, Kojima, T, Suzuki, S, Oguchi, T, Oba, M, Tsuchiya, H, Sugiura, F, Kanayama, Y, Furukawa, TA, Tokudome, S, Ishiguro, N (2009). Depression, inflammation, and pain in patients with rheumatoid arthritis. Arthritis and Rheumatism 61, 10181024.
Kozora, E, Ellison, MC, West, S (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.
Krishnaraju, K, Nguyen, HQ, Liebermann, DA, Hoffman, B (1995). The zinc finger transcription factor Egr-1 potentiates macrophage differentiation of hematopoietic cells. Molecular and Cellular Biology 15, 54995507.
Kuipers, SD, Trentani, A, Westenbroek, C, Bramham, CR, Korf, J, Kema, IP, Ter Horst, GJ, Den Boer, JA (2006). Unique patterns of FOS, phospho-CREB and BrdU immunoreactivity in the female rat brain following chronic stress and citalopram treatment. Neuropharmacology 50, 428440.
Kyriakis, JM, Avruch, J (2001). Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiological Reviews 81, 807869.
Lai, IC, Hong, CJ, Tsai, SJ (2003). Expression of cAMP response element-binding protein in major depression before and after antidepressant treatment. Neuropsychobiology 48, 182185.
Lotrich, FE (2009). Major depression during interferon-alpha treatment: vulnerability and prevention. Dialogues in Clinical Neurosciences 11, 417425.
Lutgendorf, SK, DeGeest, K, Sung, CY, Arevalo, JM, Penedo, F, Lucci, J 3rd, Goodheart, M, Lubaroff, D, Farley, DM, Sood, A, Cole, SW (2009). Depression, social support, and beta-adrenergic transcription control in human ovarian cancer. Brain, Behavior, and Immunity 23, 176183.
Maddock, C, Baita, A, Orru, MG, Sitzia, R, Costa, A, Muntoni, E, Farci, MG, Carpiniello, B, Pariante, CM (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.
Majer, M, Welberg, LA, Capuron, L, Pagnoni, G, Raison, CL, Miller, AH (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.
Manji, HK, Bebchuk, JM, Moore, GJ, Glitz, D, Hasanat, KA, Chen, G (1999). Modulation of CNS signal transduction pathways and gene expression by mood-stabilizing agents: therapeutic implications. Journal of Clinical Psychiatry 60 (Suppl. 2), 2739; discussion 40–21, 113–116.
Merritt, JA, Borden, EC, Ball, LA (1985). Measurement of 2′,5′-oligoadenylate synthetase in patients receiving interferon-alpha. Journal of Interferon Research 5, 191198.
Miller, AH (2009). Norman Cousins Lecture. Mechanisms of cytokine-induced behavioral changes: psychoneuroimmunology at the translational interface. Brain, Behavior, and Immunity 23, 149158.
Miller, GE, Chen, E, Sze, J, Marin, T, Arevalo, JM, Doll, R, Ma, R, Cole, SW (2008). A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-kappaB signaling. Biological Psychiatry 64, 266272.
Moeenrezakhanlou, A, Shephard, L, Lam, L, Reiner, NE (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.
Montgomery, SA, Asberg, M (1979). A new depression scale designed to be sensitive to change. Brtish Journal of Psychiatry 134, 382389.
Morinobu, S, Nibuya, M, Duman, RS (1995). Chronic antidepressant treatment down-regulates the induction of c-fos mRNA in response to acute stress in rat frontal cortex. Neuropsychopharmacology 12, 221228.
Musselman, DL, Lawson, DH, Gumnick, JF, Manatunga, AK, Penna, S, Goodkin, RS, Greiner, K, Nemeroff, CB, Miller, AH (2001). Paroxetine for the prevention of depression induced by high-dose interferon alfa. New England Journal of Medicine 344, 961966.
Ng, WF, Bowman, SJ (2010). Primary Sjögren's syndrome: too dry and too tired. Rheumatology (Oxford) 49, 844853.
Nijs, J, De Meirleir, K (2005). Impairments of the 2-5A synthetase/RNase L pathway in chronic fatigue syndrome. In Vivo 19, 10131021.
Okuno, T, Shindo, M, Arai, K, Matsumoto, M, Takeda, M, Kashima, K, Sokawa, Y (1991). 2′,5′-Oligoadenylate synthetase activity in peripheral blood mononuclear cells and serum during interferon treatment of chronic non-A, non-B hepatitis. Gastroenterologica Japonica 26, 603610.
Pariante, CM, Miller, AH (1995). Natural killer cell activity in major depression: a prospective study of the in vivo effects of desmethylimipramine treatment. European Neuropsychopharmacology 5 (Suppl.), 8388.
Pfeffer, LM, Dinarello, CA, Herberman, RB, Williams, BR, Borden, EC, Bordens, R, Walter, MR, Nagabhushan, TL, Trotta, PP, Pestka, S (1998). Biological properties of recombinant alpha-interferons: 40th anniversary of the discovery of interferons. Cancer Research 58, 24892499.
Potter, GG, Kittinger, JD, Wagner, HR, Steffens, DC, Krishnan, KR (2004). Prefrontal neuropsychological predictors of treatment remission in late-life depression. Neuropsychopharmacology 29, 22662271.
Raison, CL, Borisov, AS, Majer, M, Drake, DF, Pagnoni, G, Woolwine, BJ, Vogt, GJ, Massung, B, Miller, AH (2009 a). Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression. Biological Psychiatry 65, 296303.
Raison, CL, Borisov, AS, Woolwine, BJ, Massung, B, Vogt, G, Miller, AH (2010 a). Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior. Molecular Psychiatry 15, 535547.
Raison, CL, Capuron, L, Miller, AH (2006). Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends in Immunology 27, 2431.
Raison, CL, Dantzer, R, Kelley, KW, Lawson, MA, Woolwine, BJ, Vogt, G, Spivey, JR, Saito, K, Miller, AH (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.
Raison, CL, Demetrashvili, M, Capuron, L, Miller, AH (2005). Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs 19, 105123.
Raison, CL, Lin, JM, Reeves, WC (2009 b). Association of peripheral inflammatory markers with chronic fatigue in a population-based sample. Brain, Behavior, and Immunity 23, 327337.
Reeves, WC, Wagner, D, Nisenbaum, R, Jones, JF, Gurbaxani, B, Solomon, L, Papanicolaou, DA, Unger, ER, Vernon, SD, Heim, C (2005). Chronic fatigue syndrome – a clinically empirical approach to its definition and study. BMC Medicine 3, 19.
Ronnblom, L, Eloranta, ML, Alm, GV (2003). Role of natural interferon-alpha producing cells (plasmacytoid dendritic cells) in autoimmunity. Autoimmunity 36, 463472.
Saha, S, Rangarajan, PN (2003). Common host genes are activated in mouse brain by Japanese encephalitis and rabies viruses. Journal of General Virology 84, 17291735.
Sandberg, K, Eloranta, ML, Campbell, IL (1994). Expression of alpha/beta interferons (IFN-alpha/beta) and their relationship to IFN-alpha/beta-induced genes in lymphocytic choriomeningitis. Journal of Virology 68, 73587366.
Sanders, VM, Straub, RH (2002). Norepinephrine, the beta-adrenergic receptor, and immunity. Brain, Behavior, and Immunity 16, 290332.
Smets, EM, Garssen, B, Bonke, B, De Haes, JC (1995). The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. Journal of Psychosomatic Research 39, 315325.
Suhadolnik, RJ, Reichenbach, NL, Hitzges, P, Adelson, ME, Peterson, DL, Cheney, P, Salvato, P, Thompson, C, Loveless, M, Muller, WE, Schröder, HC, Strayer, DR, Carter, WA (1994 a). Changes in the 2-5A synthetase/RNase L antiviral pathway in a controlled clinical trial with poly(I)-poly(C12U) in chronic fatigue syndrome. In Vivo 8, 599604.
Suhadolnik, RJ, Reichenbach, NL, Hitzges, P, Sobol, RW, Peterson, DL, Henry, B, Ablashi, DV, Muller, WE, Schroder, HC, Carter, WA, Strayer, DR (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.
Taylor, JL, Grossberg, SE (1998). The effects of interferon-alpha on the production and action of other cytokines. Seminars in Oncology 25, 2329.
Taylor, MW, Grosse, WM, Schaley, JE, Sanda, C, Wu, X, Chien, SC, Smith, F, Wu, TG, Stephens, M, Ferris, MW, McClintick, JN, Jerome, RE, Edenberg, HJ (2004). Global effect of PEG-IFN-alpha and ribavirin on gene expression in PBMC in vitro. Journal of Interferon and Cytokine Research 24, 107118.
Trask, PC, Esper, P, Riba, M, Redman, B (2000). Psychiatric side effects of interferon therapy: prevalence, proposed mechanisms, and future directions. Journal of Clinical Oncology 18, 23162326.
Tusher, VG, Tibshirani, R, Chu, G (2001). Significance analysis of microarrays applied to the ionizing radiation response. Proceedings of the National Academy of Science USA 98, 51165121.
Vojdani, A, Ghoneum, M, Choppa, PC, Magtoto, L, Lapp, CW (1997). Elevated apoptotic cell population in patients with chronic fatigue syndrome: the pivotal role of protein kinase RNA. Journal of Internal Medicine 242, 465478.
Vojdani, A, Lapp, CW (1999). Interferon-induced proteins are elevated in blood samples of patients with chemically or virally induced chronic fatigue syndrome. Immunopharmacology and Immunotoxicology 21, 175202.
Wallace, TL, Stellitano, KE, Neve, RL, Duman, RS (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.
Wang, J, Campbell, IL, Zhang, H (2008). Systemic interferon-alpha regulates interferon-stimulated genes in the central nervous system. Molecular Psychiatry 13, 293301.
Wang, J, Dunn, AJ, Roberts, AJ, Zhang, H (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.
Wichers, MC, Koek, GH, Robaeys, G, Praamstra, AJ, Maes, M (2005). Early increase in vegetative symptoms predicts IFN-alpha-induced cognitive-depressive changes. Psychological Medicine 35, 433441.
Yamada, S, Yamamoto, M, Ozawa, H, Riederer, P, Saito, T (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.
Yirmiya, R, Pollak, Y, Morag, M, Reichenberg, A, Barak, O, Avitsur, R, Shavit, Y, Ovadia, H, Weidenfeld, J, Morag, A, Newman, ME, Pollmächer, T (2000). Illness, cytokines, and depression. Annals of the New York Academy of Sciences 917, 478487.
Zarubin, T, Han, J (2005). Activation and signaling of the p38 MAP kinase pathway. Cell Research 15, 1118.


Type Description Title
Supplementary Tables

Felger Supplementary Table 1
Supplementary Table S1. Gene transcripts significantly up- and down-regulated in subjects administered 12 weeks IFN-alpha and ribavirin (n=11) compared to controls (n=10) as identified by SAM.

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Supplementary Tables

Felger Supplementary Table 2
Supplementary Table S2. Ingenuity canonical pathways analysis of genes differentially regulated by IFN-alpha.

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Supplementary Tables

Felger Supplementary Table 3
Supplementary Table S3. Gene transcripts up- and down-regulated by 50% (≥1.5 fold) in IFN-alpha-treated subjects (n=11) compared to control (n=10), and in subjects with high (n=4) versus low (n=7) MADRS and MFI scores at 12 weeks IFN-alpha.

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Supplementary Tables

Felger Supplementary Material
Felger Supplementary Material

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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)...


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