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Rapid Regulation of Depression-Associated Genes in a New Mouse Model Mimicking Interferon-α-Related Depression in Hepatitis C Virus Infection

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Abstract

Major depression is a serious side effect of interferon-α (IFN-α), which is used in the therapy of hepatitis C virus (HCV) infection. Due to the lack of reproducible animal models, the mechanisms underlying IFN-α-related depression are largely unknown. We herein established a mouse model, in which murine IFN-α (250 IU/day) and polyinosinic/polycytidylic acid (poly(I:C); 1 μg/day), a toll-like receptor-3 (TLR3) agonist that mimics the effect of HCV double-strand RNA, were continuously infused into the lateral ventricle via miniosmotic pumps over up to 14 days. The delivery of IFN-α and poly(I:C), but not of IFN-α or poly(I:C) alone, resulted in a reproducible depression-like state that was characterized by reduced exploration behavior in open-field tests, increased immobility in tail suspension and forced swimming tests, and a moderate loss of body weight. In the hippocampus and prefrontal cortex, the pro-inflammatory genes TNF-α, IL-6, tissue inhibitor of metalloproteinases-1 (Timp-1), CXC motif ligand-1 (Cxcl1), Cxcl10, and CC motif ligand-5 (Ccl5) were synergistically induced by IFN-α and poly(I:C), most pronounced after 14-day exposure. In comparison, the interferon-inducible genes of signal transducer and activator of transcription-1 (Stat1), guanylate binding protein-1 (Gbp1), proteasome subunit-β type-9 (Psmb9), ubiquitin-conjugating enzyme E2L-6 (Ube2l6), receptor transporter protein-4 (Rtp4), and GTP cyclohydrolase-1 (Gch1), which had previously been elevated in the blood of IFN-α-treated patients developing depression, in the brains of suicidal individuals, and in primary neurons exposed to IFN-α and poly(I:C), were induced even earlier, reaching maximum levels mostly after 24 hours. We propose that interferon-inducible genes might be useful markers of imminent depression.

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References

  1. Hoofnagle JH (2002) Course and outcome of hepatitis C. Hepatology 36:S21–S29

    Article  PubMed  Google Scholar 

  2. Fried MW, Shiffman ML, Reddy KR et al (2002) Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347:975–982

    Article  CAS  PubMed  Google Scholar 

  3. Keefe B (2007) Interferon-induced depression in hepatitis C: an update. Curr Psychiatry Rep 9:255–261

    Article  PubMed  Google Scholar 

  4. Yu ML, Dai CY, Lee LP et al (2006) Outcome of chronic hepatitis C patients who required early termination of pegylated interferon-alpha plus ribavirin combination therapy. Antivir Ther 11:1015–1019

    CAS  PubMed  Google Scholar 

  5. Schaefer M, Capuron L, Friebe A et al (2012) Hepatitis C infection, antiviral treatment and mental health: a European expert consensus statement. J Hepatol 57:1379–1390

    Article  PubMed  Google Scholar 

  6. Guan R (2005) Treatment of chronic hepatitis B infection using interferon. Med J Malaysia 60(Suppl B):28–33

    PubMed  Google Scholar 

  7. Pasquali S, Mocellin S (2010) The anticancer face of interferon alpha (IFN-alpha): from biology to clinical results, with a focus on melanoma. Curr Med Chem 17:3327–3336

    Article  CAS  PubMed  Google Scholar 

  8. Raison CL, Borisov AS, Broadwell SD, Capuron L, Woolwine BJ, Jacobson IM, Nemeroff CB, Miller AH (2005) Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction. J Clin Psychiatry 66:41–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cacciarelli TV, Martinez OM, Gish RG, Villanueva JC, Krams SM (1996) Immunoregulatory cytokines in chronic hepatitis C virus infection: pre- and posttreatment with interferon alfa. Hepatology 24:6–9

    Article  CAS  PubMed  Google Scholar 

  10. Wichers MC, Kenis G, Koek GH, Robaeys G, Nicolson NA, Maes M (2007) Interferon-alpha-induced depressive symptoms are related to changes in the cytokine network but not to cortisol. J Psychosom Res 62:207–214

    Article  PubMed  Google Scholar 

  11. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL (2010) A meta-analysis of cytokines in major depression. Biol Psychiatry 67:446–457

    Article  CAS  PubMed  Google Scholar 

  12. Rethorst CD, Toups MS, Greer TL, Nakonezny PA, Carmody TJ, Grannemann BD, Huebinger RM, Barber RC, Trivedi MH (2013) Pro-inflammatory cytokines as predictors of antidepressant effects of exercise in major depressive disorder. Mol Psychiatry 18:1119–1124

    Article  CAS  PubMed  Google Scholar 

  13. Miller AH, Maletic V, Raison CL (2009) Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 65:732–741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Raison CL, Capuron L, Miller AH (2006) Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 27:24–31

    Article  CAS  PubMed  Google Scholar 

  15. Monaco S, Ferrari S, Gajofatto A, Zanusso G, Mariotto S (2012) HCV-related nervous system disorders. Clin Dev Immunol 2012:236148

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wilkinson J, Radkowski M, Eschbacher JM, Laskus T (2010) Activation of brain macrophages/microglia cells in hepatitis C infection. Gut 59:1394–1400

    Article  CAS  PubMed  Google Scholar 

  17. Bsibsi M, Ravid R, Gveric D, van Noort JM (2002) Broad expression of toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol 61:1013–1021

    Article  CAS  PubMed  Google Scholar 

  18. Cameron JS, Alexopoulou L, Sloane JA et al (2007) Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals. J Neurosci 27:13033–13041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jack CS, Arbour N, Manusow J, Montgrain V, Blain M, McCrea E, Shapiro A, Antel JP (2005) TLR signaling tailors innate immune responses in human microglia and astrocytes. J Immunol 175:4320–4330

    Article  CAS  PubMed  Google Scholar 

  20. Olson JK, Miller SD (2004) Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 173:3916–3924

    Article  CAS  PubMed  Google Scholar 

  21. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-kappaB by toll-like receptor 3. Nature 413:732–738

    Article  CAS  PubMed  Google Scholar 

  22. Carpentier PA, Begolka WS, Olson JK, Elhofy A, Karpus WJ, Miller SD (2005) Differential activation of astrocytes by innate and adaptive immune stimuli. Glia 49:360–374

    Article  PubMed  Google Scholar 

  23. Hoyo-Becerra C, Huebener A, Trippler M et al (2013) Concomitant interferon alpha stimulation and TLR3 activation induces neuronal expression of depression-related genes that are elevated in the brain of suicidal persons. PLoS One 8:e83149

    Article  PubMed  PubMed Central  Google Scholar 

  24. Lafon M, Megret F, Lafage M, Prehaud C (2006) The innate immune facet of brain: human neurons express TLR-3 and sense viral dsRNA. J Mol Neurosci 29:185–194

    Article  CAS  PubMed  Google Scholar 

  25. Schlaak JF, Trippler M, Hoyo-Becerra C, Erim Y, Kis B, Wang B, Scherbaum N, Gerken G (2012) Selective hyper-responsiveness of the interferon system in major depressive disorders and depression induced by interferon therapy. PLoS One 7:e38668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Anisman H, Hayley S (2012) Inflammatory factors contribute to depression and its comorbid conditions. Sci Signal 5:e45

    Article  Google Scholar 

  27. Hayley S, Scharf J, Anisman H (2013) Central administration of murine interferon-alpha induces depressive-like behavioral, brain cytokine and neurochemical alterations in mice: a mini-review and original experiments. Brain Behav Immun 31:115–127

    Article  CAS  PubMed  Google Scholar 

  28. Kosel M, Bilkei-Gorzo A, Zawatzky R, Zimmer A, Schlaepfer TE (2011) Pegylated human interferon alpha 2a does not induce depression-associated changes in mice. Psychiatry Res 185:243–247

    Article  CAS  PubMed  Google Scholar 

  29. Zhang H, Tian Z, Wang J (2010) Behavioral evaluation of transgenic mice with CNS expression of IFN-alpha by elevated plus-maze and Porsolt swim test. Neurosci Lett 479:287–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Okun E, Griffioen K, Barak B et al (2010) Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis. Proc Natl Acad Sci U S A 107:15625–15630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berlin) 85:367–370

    Article  CAS  Google Scholar 

  32. Borsini F (1995) Role of the serotonergic system in the forced swimming test. Neurosci Biobehav Rev 19:377–395

    Article  CAS  PubMed  Google Scholar 

  33. Capuron L, Ravaud A, Dantzer R (2001) Timing and specificity of the cognitive changes induced by interleukin-2 and interferon-alpha treatments in cancer patients. Psychosom Med 63:376–386

    Article  CAS  PubMed  Google Scholar 

  34. 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 Behav Immun 25:1094–1098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Friebe A, Schwarz MJ, Schmid-Wendtner M, Volkenandt M, Schmidt F, Horn M, Janssen G, Schaefer M (2007) Pretreatment levels of sTNF-R1 and sIL-6R are associated with a higher vulnerability for IFN-alpha-induced depressive symptoms in patients with malignant melanoma. J Immunother 30:333–337

    Article  CAS  PubMed  Google Scholar 

  36. Fahey B, Hickey B, Kelleher D, O’Dwyer AM, O’Mara SM (2007) The widely-used anti-viral drug interferon-alpha induces depressive- and anxiogenic-like effects in healthy rats. Behav Brain Res 182:80–87

    Article  CAS  PubMed  Google Scholar 

  37. Ping F, Shang J, Zhou J, Zhang H, Zhang L (2012) 5-HT(1A) receptor and apoptosis contribute to interferon-alpha-induced “depressive-like” behavior in mice. Neurosci Lett 514:173–178

    Article  CAS  PubMed  Google Scholar 

  38. Fishman SL, Murray JM, Eng FJ, Walewski JL, Morgello S, Branch AD (2008) Molecular and bioinformatic evidence of hepatitis C virus evolution in brain. J Infect Dis 197:597–607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wilkinson J, Radkowski M, Laskus T (2009) Hepatitis C virus neuroinvasion: identification of infected cells. J Virol 83:1312–1319

    Article  CAS  PubMed  Google Scholar 

  40. Felger JC, Alagbe O, Hu F et al (2007) Effects of interferon-alpha on rhesus monkeys: a nonhuman primate model of cytokine-induced depression. Biol Psychiatry 62:1324–1333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Orsal AS, Blois SM, Bermpohl D, Schaefer M, Coquery N (2008) Administration of interferon-alpha in mice provokes peripheral and central modulation of immune cells, accompanied by behavioral effects. Neuropsychobiology 58:211–222

    Article  CAS  PubMed  Google Scholar 

  42. Dunn AJ, Swiergiel AH, de Beaurepaire R (2005) Cytokines as mediators of depression: what can we learn from animal studies? Neurosci Biobehav Rev 29:891–909

    Article  CAS  PubMed  Google Scholar 

  43. Pasco JA, Nicholson GC, Williams LJ, Jacka FN, Henry MJ, Kotowicz MA, Schneider HG, Leonard BE, Berk M (2010) Association of high-sensitivity C-reactive protein with de novo major depression. Br J Psychiatry 197:372–377

    Article  PubMed  Google Scholar 

  44. Weissenborn K, Tryc AB, Heeren M, Worthmann H, Pflugrad H, Berding G, Bokemeyer M, Tillmann HL, Goldbecker A (2009) Hepatitis C virus infection and the brain. Metab Brain Dis 24:197–210

    Article  PubMed  Google Scholar 

  45. Hannestad J, DellaGioia N, Bloch M (2011) The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology 36:2452–2459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hiles SA, Baker AL, de Malmanche T, Attia J (2012) A meta-analysis of differences in IL-6 and IL-10 between people with and without depression: exploring the causes of heterogeneity. Brain Behav Immun 26:1180–1188

    Article  CAS  PubMed  Google Scholar 

  47. Howren MB, Lamkin DM, Suls J (2009) Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 71:171–186

    Article  CAS  PubMed  Google Scholar 

  48. Levine J, Barak Y, Chengappa KN, Rapoport A, Rebey M, Barak V (1999) Cerebrospinal cytokine levels in patients with acute depression. Neuropsychobiology 40:171–176

    Article  CAS  PubMed  Google Scholar 

  49. Osuka K, Watanabe Y, Usuda N, Atsuzawa K, Yasuda M, Aoshima C, Wakabayashi T, Takayasu M (2011) Activation of STAT1 in neurons following spinal cord injury in mice. Neurochem Res 36:2236–2243

    Article  CAS  PubMed  Google Scholar 

  50. Dedoni S, Olianas MC, Onali P (2010) Interferon-beta induces apoptosis in human SH-SY5Y neuroblastoma cells through activation of JAK-STAT signaling and down-regulation of PI3K/Akt pathway. J Neurochem 115:1421–1433

    Article  CAS  PubMed  Google Scholar 

  51. Schindler C, Brutsaert S (1999) Interferons as a paradigm for cytokine signal transduction. Cell Mol Life Sci 55:1509–1522

    Article  CAS  PubMed  Google Scholar 

  52. Miller AH (2009) Norman cousins lecture. Mechanisms of cytokine-induced behavioral changes: psychoneuroimmunology at the translational interface. Brain Behav Immun 23:149–158

    Article  CAS  PubMed  Google Scholar 

  53. Hammon M, Herrmann M, Bleiziffer O et al (2011) Role of guanylate binding protein-1 in vascular defects associated with chronic inflammatory diseases. J Cell Mol Med 15:1582–1592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Larrea E, Aldabe R, Gonzalez I, Segura V, Sarobe P, Echeverria I, Prieto J (2009) Oncostatin M enhances the antiviral effects of type I interferon and activates immunostimulatory functions in liver epithelial cells. J Virol 83:3298–3311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Huber C, Fuchs D, Hausen A, Margreiter R, Reibnegger G, Spielberger M, Wachter H (1983) Pteridines as a new marker to detect human T cells activated by allogeneic or modified self major histocompatibility complex (MHC) determinants. J Immunol 130:1047–1050

    CAS  PubMed  Google Scholar 

  56. Huber C, Batchelor JR, Fuchs D et al (1984) Immune response-associated production of neopterin. Release from macrophages primarily under control of interferon-gamma. J Exp Med 160:310–316

    Article  CAS  PubMed  Google Scholar 

  57. Hoyo-Becerra C, Schlaak JF, Hermann DM (2014) Insights from interferon-alpha-related depression for the pathogenesis of depression associated with inflammation. Brain Behav Immun. doi:10.1016/j.bbi.2014.06.200

    PubMed  Google Scholar 

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Acknowledgments

We want to thank Mrs. Kathrin Kleinehr and Mrs. Lena Poggenpohl for excellent technical assistance and to outline the exceptional help of Mr. Anthony Squire, manager of the Imaging Facility of the Clinic hospital of Essen, in the acquisition and analysis of the pictures.

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The authors declare that they have no conflict of interest.

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Correspondence to Dirk M. Hermann.

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Carolina Hoyo-Becerra, Zijian Liu, Dirk M. Hermann, and Joerg F. Schlaak contributed equally to this work.

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Online Resource 1

Dose-response evaluation of mIFN-α and poly(I:C) following intracerebroventricular delivery. Response of the interferon response gene Stat1 in the hippocampus and prefrontal cortex 24 h after intracerebroventricular infusion of mIFN-α or poly(I:C). Data are copy numbers, evaluated by RT-PCR, that were normalized with the house-keeping gene β-actin. Based on the concentration yielding the maximum response, EC25 doses (250 IU mIFN-α), 1 μg poly(I:C)) were determined that were used as daily doses in subsequent experiments. Data are mean values ± S.E.M. (PDF 119 kb)

Online Resource 2

Mild body weight loss as correlate of depressive phenotype in mice receiving combined mIFN-α and poly(I:C) exposure. Change of mouse body weight during 14 days exposure to mIFN-α (250 IU/day), poly(I:C) (1 μg/day) or both. Data are mean values ± S.E.M., evaluated by oneway ANOVA followed by Tukey’s posthoc tests (n = 12 animals per group). **p ≤ 0.05 compared with vehicle. (PDF 69 kb)

Online Resource 3

DRIIs without response to combined intracerebroventricular mIFN-α and poly(I:C) exposure. Fold changes of Tnfsf10, Mef2a and Dynlt1 mRNA in total RNA extracts isolated from the hippocampus (HP) and prefrontal cortex (PC) of mice after 24 h or 14 days exposure to mIFN (250 IU/day), poly(I:C) (1 μg/day) or both, as evaluated by RT-PCR. Data are mean values ± S.E.M. (n = 6 animals per group). No significant differences were found in oneway ANOVA followed by Tukey’s posthoc tests. (PDF 198 kb)

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Hoyo-Becerra, C., Liu, Z., Yao, J. et al. Rapid Regulation of Depression-Associated Genes in a New Mouse Model Mimicking Interferon-α-Related Depression in Hepatitis C Virus Infection. Mol Neurobiol 52, 318–329 (2015). https://doi.org/10.1007/s12035-014-8861-z

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