Hostname: page-component-745bb68f8f-b95js Total loading time: 0 Render date: 2025-01-25T18:52:54.507Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  09 December 2011

J. C. Felger ,
S. W. Cole ,
T. W. W. Pace ,
F. Hu ,
B. J. Woolwine ,
G. H. Doho ,
C. L. Raison  and
A. H. Miller
J. C. Felger*
Affiliation:
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA The Winship Cancer Institute, Emory University, Atlanta, GA, USA
S. W. Cole
Affiliation:
Department of Medicine, Division of Hematology-Oncology, University of California, Los Angeles School of Medicine, Los Angeles, CA, USA Biology Institute and Jonsson Comprehensive Cancer Center, University of California, Los Angeles AIDS Institute, Los Angeles, CA, USA Cousins Center, University of California, Los Angeles, CA, USA
T. W. W. Pace
Affiliation:
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA The Winship Cancer Institute, Emory University, Atlanta, GA, USA
F. Hu
Affiliation:
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA The Winship Cancer Institute, Emory University, Atlanta, GA, USA
B. J. Woolwine
Affiliation:
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA The Winship Cancer Institute, Emory University, Atlanta, GA, USA
G. H. Doho
Affiliation:
Genomics Shared Resource, Emory University, Atlanta, GA, USA
C. L. Raison
Affiliation:
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA The Winship Cancer Institute, Emory University, Atlanta, GA, USA
A. H. Miller
Affiliation:
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA The Winship Cancer Institute, Emory University, Atlanta, GA, USA
*
*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)
Get access Rights & Permissions [Opens in a new window]

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.

Keywords

Depressionfatiguegene arrayinterferon-α2′-5′-oligoadenylate synthetase
Type
Original Articles
Information
Psychological Medicine , Volume 42 , Issue 8 , August 2012 , pp. 1591 - 1603
Copyright
Copyright © Cambridge University Press 2011

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

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, 5016–5026.Google Scholar
Blendy, JA (2006). The role of CREB in depression and antidepressant treatment. Biological Psychiatry 59, 1144–1150.CrossRefGoogle ScholarPubMed
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, 185–193.Google Scholar
Bower, JE, Ganz, PA, Aziz, N, Fahey, JL (2002). Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosomatic Medicine 64, 604–611.CrossRefGoogle ScholarPubMed
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, 147–150.Google Scholar
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, 599–617.Google Scholar
Cole, SW, Galic, Z, Zack, JA (2003). Controlling false-negative errors in microarray differential expression analysis: a PRIM approach. Bioinformatics 19, 1808–1816.Google Scholar
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, 3080–3085.Google Scholar
Cole, SW, Yan, W, Galic, Z, Arevalo, J, Zack, JA (2005). Expression-based monitoring of transcription factor activity: the TELiS database. Bioinformatics 21, 803–810.CrossRefGoogle ScholarPubMed
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, 1415–1421.Google Scholar
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, 175–189.CrossRefGoogle Scholar
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, 388–395.Google Scholar
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, 1094–1098.Google Scholar
First, MB, Spitzer, RL, Gibbon, M, Williams, JB (1997). Structured Clinical Interview for DSM-IV. American Psychiatric Press: Washington, DC.Google Scholar
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, 189–198.CrossRefGoogle Scholar
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, 2770–2775.CrossRefGoogle ScholarPubMed
Haque, SJ, Williams, BR (1998). Signal transduction in the interferon system. Seminars in Oncology 25, 14–22.Google Scholar
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, 22–30.CrossRefGoogle ScholarPubMed
Kearns, NP, Cruickshank, CA, McGuigan, KJ, Riley, SA, Shaw, SP, Snaith, RP (1982). A comparison of depression rating scales. British Journal of Psychiatry 141, 45–49.CrossRefGoogle ScholarPubMed
Klimas, NG, Koneru, AO (2007). Chronic fatigue syndrome: inflammation, immune function, and neuroendocrine interactions. Current Rheumatology Reports 9, 482–487.CrossRefGoogle ScholarPubMed
Klimas, NG, Salvato, FR, Morgan, R, Fletcher, MA (1990). Immunologic abnormalities in chronic fatigue syndrome. Journal of Clinical Microbiology 28, 1403–1410.CrossRefGoogle ScholarPubMed
Koch, JM, Kell, S, Hinze-Selch, D, Aldenhoff, JB (2002). Changes in CREB-phosphorylation during recovery from major depression. Journal of Psychiatric Research 36, 369–375.CrossRefGoogle ScholarPubMed
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, 1018–1024.Google Scholar
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, 628–635.Google Scholar
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, 5499–5507.Google Scholar
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, 428–440.CrossRefGoogle ScholarPubMed
Kyriakis, JM, Avruch, J (2001). Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiological Reviews 81, 807–869.CrossRefGoogle Scholar
Lai, IC, Hong, CJ, Tsai, SJ (2003). Expression of cAMP response element-binding protein in major depression before and after antidepressant treatment. Neuropsychobiology 48, 182–185.CrossRefGoogle ScholarPubMed
Lotrich, FE (2009). Major depression during interferon-alpha treatment: vulnerability and prevention. Dialogues in Clinical Neurosciences 11, 417–425.Google Scholar
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, 176–183.Google Scholar
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, 41–46.CrossRefGoogle Scholar
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, 870–880.Google Scholar
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), 27–39; discussion 40–21, 113–116.Google Scholar
Merritt, JA, Borden, EC, Ball, LA (1985). Measurement of 2′,5′-oligoadenylate synthetase in patients receiving interferon-alpha. Journal of Interferon Research 5, 191–198.CrossRefGoogle ScholarPubMed
Miller, AH (2009). Norman Cousins Lecture. Mechanisms of cytokine-induced behavioral changes: psychoneuroimmunology at the translational interface. Brain, Behavior, and Immunity 23, 149–158.Google Scholar
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, 266–272.Google Scholar
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, 519–528.CrossRefGoogle ScholarPubMed
Montgomery, SA, Asberg, M (1979). A new depression scale designed to be sensitive to change. Brtish Journal of Psychiatry 134, 382–389.Google Scholar
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, 221–228.Google Scholar
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, 961–966.Google Scholar
Ng, WF, Bowman, SJ (2010). Primary Sjögren's syndrome: too dry and too tired. Rheumatology (Oxford) 49, 844–853.Google Scholar
Nijs, J, De Meirleir, K (2005). Impairments of the 2-5A synthetase/RNase L pathway in chronic fatigue syndrome. In Vivo 19, 1013–1021.Google ScholarPubMed
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, 603–610.CrossRefGoogle ScholarPubMed
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.), 83–88.Google Scholar
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, 2489–2499.Google ScholarPubMed
Potter, GG, Kittinger, JD, Wagner, HR, Steffens, DC, Krishnan, KR (2004). Prefrontal neuropsychological predictors of treatment remission in late-life depression. Neuropsychopharmacology 29, 2266–2271.Google Scholar
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, 296–303.CrossRefGoogle ScholarPubMed
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, 535–547.CrossRefGoogle ScholarPubMed
Raison, CL, Capuron, L, Miller, AH (2006). Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends in Immunology 27, 24–31.CrossRefGoogle ScholarPubMed
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, 393–403.Google Scholar
Raison, CL, Demetrashvili, M, Capuron, L, Miller, AH (2005). Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs 19, 105–123.CrossRefGoogle Scholar
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, 327–337.CrossRefGoogle Scholar
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.Google Scholar
Ronnblom, L, Eloranta, ML, Alm, GV (2003). Role of natural interferon-alpha producing cells (plasmacytoid dendritic cells) in autoimmunity. Autoimmunity 36, 463–472.Google Scholar
Saha, S, Rangarajan, PN (2003). Common host genes are activated in mouse brain by Japanese encephalitis and rabies viruses. Journal of General Virology 84, 1729–1735.Google Scholar
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, 7358–7366.CrossRefGoogle ScholarPubMed
Sanders, VM, Straub, RH (2002). Norepinephrine, the beta-adrenergic receptor, and immunity. Brain, Behavior, and Immunity 16, 290–332.CrossRefGoogle ScholarPubMed
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, 315–325.CrossRefGoogle ScholarPubMed
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, 599–604.Google Scholar
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.CrossRefGoogle ScholarPubMed
Taylor, JL, Grossberg, SE (1998). The effects of interferon-alpha on the production and action of other cytokines. Seminars in Oncology 25, 23–29.Google Scholar
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, 107–118.CrossRefGoogle ScholarPubMed
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, 2316–2326.Google Scholar
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, 5116–5121.CrossRefGoogle Scholar
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, 465–478.CrossRefGoogle ScholarPubMed
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, 175–202.CrossRefGoogle ScholarPubMed
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, 151–160.CrossRefGoogle ScholarPubMed
Wang, J, Campbell, IL, Zhang, H (2008). Systemic interferon-alpha regulates interferon-stimulated genes in the central nervous system. Molecular Psychiatry 13, 293–301.Google Scholar
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.Google Scholar
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, 433–441.CrossRefGoogle ScholarPubMed
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, 671–680.Google Scholar
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, 478–487.CrossRefGoogle ScholarPubMed
Zarubin, T, Han, J (2005). Activation and signaling of the p38 MAP kinase pathway. Cell Research 15, 11–18.Google Scholar
Supplementary material: File

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.

Download Felger Supplementary Table 1(File)
File 584.7 KB
Supplementary material: File

Felger Supplementary Table 2

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

Download Felger Supplementary Table 2(File)
File 37.4 KB
Supplementary material: File

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.

Download Felger Supplementary Table 3(File)
File 806.4 KB
Supplementary material: File

Felger Supplementary Material

Felger Supplementary Material

Download Felger Supplementary Material(File)
File 15.8 KB