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Systemic interferon-α regulates interferon-stimulated genes in the central nervous system

Molecular Psychiatry volume 13, pages 293–301 (2008)Cite this article

Abstract

The prime anti-viral cytokine interferon-α (IFN-α) has been implicated in several central nervous system (CNS) disorders in addition to its beneficial effects. Systemic IFN-α treatment causes severe neuropsychiatric complications in humans, including depression, anxiety and cognitive impairments. While numerous neuromodulatory effects by IFN-α have been described, it remains unresolved whether or not systemic IFN-α acts directly on the brain to execute its CNS actions. In the present study, we have analyzed the genes directly regulated in post-IFN-α receptor signaling and found that intraperitoneal administration of mouse IFN-α, but not human IFN-α, activated expression of several prototypic IFN-stimulated genes (ISGs), in particular signal transducers and activators of transcription (STAT1), IFN-induced 15 kDa protein (ISG15), ubiquitin-specific proteinase 18 (USP18) and guanylate-binding protein 3 (GBP3) in the brain. A similar temporal profile for the regulated expression of these IFN-α-activated ISG genes was observed in the brain compared with the peripheral organs. Dual labeling in situ hybridization combined with immunocytochemical staining demonstrated a wide distribution of the key IFN-regulated gene STAT1 transcripts in the different parenchyma cells of the brain, particularly neurons. The overall response to IFN-α challenge was abolished in STAT1 knockout mice. Together, our results indicate a direct, STAT1-dependent action of systemic IFN-α in the CNS, which may provide the basis for a mechanism in humans for neurological/neuropsychiatric illnesses associated with IFN-α therapy.

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References

  1. Pestka S . The human interferon alpha species and receptors. Biopolymers 2000; 55: 254–287.

    Article  CAS  Google Scholar 

  2. Calvet MC, Gresser I . Interferon enhances the excitability of cultured neurones. Nature 1979; 278: 558–560.

    Article  CAS  Google Scholar 

  3. Krueger JM, Dinarello CA, Shoham S, Davenne D, Walter J, Kubillus S . Interferon alpha-2 enhances slow-wave sleep in rabbits. Int J Immunopharmacol 1987; 9: 23–30.

    Article  CAS  Google Scholar 

  4. Koyanagi S, Ohdo S . Alteration of intrinsic biological rhythms during interferon treatment and its possible mechanism. Mol Pharmacol 2002; 62: 1393–1399.

    Article  CAS  Google Scholar 

  5. Plata-Salaman CR . Interferons and central regulation of feeding. Am J Physiol 1992; 263 (Part 2): R1222–R1227.

    CAS  PubMed  Google Scholar 

  6. Schrott LM, Crnic LS . Increased anxiety behaviors in autoimmune mice. Behav Neurosci 1996; 110: 492–502.

    Article  CAS  Google Scholar 

  7. Krivine A, Force G, Servan J, Cabee A, Rozenberg F, Dighiero L et al. Measuring HIV-1 RNA and interferon-alpha in the cerebrospinal fluid of AIDS patients: insights into the pathogenesis of AIDS Dementia Complex. J Neurovirol 1999; 5: 500–506.

    Article  CAS  Google Scholar 

  8. Shiozawa S, Kuroki Y, Kim M, Hirohata S, Ogino T . Interferon-alpha in lupus psychosis. Arthritis Rheum 1992; 35: 417–422.

    Article  CAS  Google Scholar 

  9. Lebon P, Badoual J, Ponsot G, Goutieres F, Hemeury-Cukier F, Aicardi J . Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy. J Neurol Sci 1988; 84: 201–208.

    Article  CAS  Google Scholar 

  10. Schaefer M, Engelbrecht MA, Gut O, Fiebich BL, Bauer J, Schmidt F et al. Interferon alpha (IFNa) and psychiatric syndromes: a review. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 731–746.

    Article  CAS  Google Scholar 

  11. Raison CL, Demetrashvili M, Capuron L, Miller AH . Neuropsychiatric adverse effects of interferon-α: recognition and management. CNS Drugs 2005; 19: 105–123.

    Article  CAS  Google Scholar 

  12. Kitagami T, Yamada K, Miura H, Hashimoto R, Nabeshima T, Ohta T . Mechanism of systemically injected interferon-alpha impeding monoamine biosynthesis in rats: role of nitric oxide as a signal crossing the blood-brain barrier. Brain Res 2003; 978: 104–114.

    Article  CAS  Google Scholar 

  13. Makino M, Kitano Y, Hirohashi M, Takasuna K . Enhancement of immobility in mouse forced swimming test by treatment with human interferon. Eur J Pharmacol 1998; 356: 1–7.

    Article  CAS  Google Scholar 

  14. Juengling FD, Ebert D, Gut O, Engelbrecht MA, Rasenack J, Nitzsche EU et al. Prefrontal cortical hypometabolism during low-dose interferon alpha treatment. Psychopharmacology 2000; 152: 383–389.

    Article  CAS  Google Scholar 

  15. Capuron L, Pagnoni G, Demetrashvili M, Woolwine BJ, Nemeroff CB, Berns GS et al. Anterior cingulate activation and error processing during interferon-alpha treatment. Biol Psychiatry 2005; 58: 190–196.

    Article  CAS  Google Scholar 

  16. Billiau A, Heremans H, Ververken D, van Damme J, Carton H, de Somer P . Tissue distribution of human interferons after exogenous administration in rabbits, monkeys, and mice. Arch Virol 1981; 68: 19–25.

    Article  CAS  Google Scholar 

  17. Collins JM, Riccardi R, Trown P, O'Neill D, Poplack DG . Plasma and cerebrospinal fluid pharmacokinetics of recombinant interferon alpha A in monkeys: comparison of intravenous, intramuscular, and intraventricular delivery. Cancer Drug Deliv 1985; 2: 247–253.

    Article  CAS  Google Scholar 

  18. Banks WA, Kastin AJ, Broadwell RD . Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation 1995; 2: 241–248.

    Article  CAS  Google Scholar 

  19. Maier SF, Watkins LR . Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol Rev 1998; 105: 83–107.

    Article  CAS  Google Scholar 

  20. Reyes-Vazquez C, Prieto-Gomez B, Dafny N . Alpha-interferon suppresses food intake and neuronal activity of the lateral hypothalamus. Neuropharmacology 1994; 33: 1545–1552.

    Article  CAS  Google Scholar 

  21. Terao A, Oikawa M, Saito M . Cytokine-induced change in hypothalamic norepinephrine turnover: involvement of corticotropin-releasing hormone and prostaglandins. Brain Res 1993; 622: 257–261.

    Article  CAS  Google Scholar 

  22. Darnell Jr JE, Kerr IM, Stark GR . Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994; 264: 1415–1421.

    Article  CAS  Google Scholar 

  23. Stark GR, Kerr IM, Williams BRG, Silverman RH, Schreiber RD . How cells respond to interferons. Ann Rev Biochem 1998; 67: 227–264.

    Article  CAS  Google Scholar 

  24. Der SD, Zhou A, Williams BRG, Silverman RH . Identification of genes differentially regulated by interferon α, β, or γ using oligonucleotide arrays. Proc Natl Acad Sci USA 1998; 95: 15623–15628.

    Article  CAS  Google Scholar 

  25. Wang J, Campbell IL . Innate STAT1-dependent genomic response of neurons to the antiviral cytokine alpha interferon. J Virol 2005; 79: 8295–8302.

    Article  CAS  Google Scholar 

  26. Wang J, Pham-Mitchell N, Schindler C, CampbelI IL . Dysregulated Sonic hedgehog signaling and medulloblastoma consequent to IFN-α-stimulated STAT2-independent production of IFN-γ in the brain. J Clin Invest 2003; 112: 535–543.

    Article  CAS  Google Scholar 

  27. Maier J, Kincaid C, Pagenstecher A, Campbell IL . Regulation of signal transducer and activator of transcription and suppressor of cytokine-signaling gene expression in the brain of mice with astrocyte-targeted production of interleukin-12 or experimental autoimmune encephalomyelitis. Am J Pathol 2002; 160: 271–288.

    Article  CAS  Google Scholar 

  28. Trask PC, Esper P, Riba M, Redman B . Psychiatric side effects of interferon therapy: prevalence, proposed mechanisms, and future directions. J Clin Oncol 2000; 18: 2316–2326.

    Article  CAS  Google Scholar 

  29. Jonasch E, Haluska FG . Interferon in oncological practice: review of interferon biology, clinical applications, and toxicities. Oncologist 2001; 6: 34–55.

    Article  CAS  Google Scholar 

  30. Yamano M, Yuki H, Yasuda S, Miyata K . Corticotropin-releasing hormone receptors mediate consensus interferon-a YM643-induced depression-like behavior in mice. J Pharmacol Exp Ther 2000; 292: 181–187.

    CAS  PubMed  Google Scholar 

  31. Makino M, Kitano Y, Komiyama C, Hirohashi M, Takasuna K . Involvement of central opioid systems in human interferon-a induced immobility in the mouse forced swimming test. Br J Pharmacol 2000; 130: 1269–1274.

    Article  CAS  Google Scholar 

  32. Trown PW, Wills RJ, Kamm JJ . The preclinical development of Roferon-A. Cancer 1986; 57 (8 Suppl): 1648–1656.

    Article  CAS  Google Scholar 

  33. Zoon KC, Miller D, Bekisz J, zur Nedden D, Enterline JC, Nguyen NY et al. Purification and characterization of multiple components of human lymphoblastoid interferon-α. J Biol Chem 1992; 267: 15210–15216.

    CAS  PubMed  Google Scholar 

  34. Platanias LC, Fish EN . Signaling pathways activated by interferons. Exp Hematol 1999; 27: 1583–1592.

    Article  CAS  Google Scholar 

  35. Wang J, Schreiber RD, Campbell IL . STAT1 deficiency unexpectedly and markedly exacerbates the pathophysiological actions of IFN-α in the central nervous system. Proc Natl Acad Sci USA 2002; 99: 16209–16214.

    Article  CAS  Google Scholar 

  36. Blalock JE, Smith EM . Human leukocyte interferon: structural and biological relatedness to adrenocorticotropic hormone and endorphins. Proc Natl Acad Sci USA 1980; 77: 5972–5974.

    Article  CAS  Google Scholar 

  37. Dinarello CA, Bernheim HA, Duff GW, Le HV, Nagabhushan TL, Hamilton NC et al. Mechanisms of fever induced by recombinant human interferon. J Clin Invest 1984; 74: 906–913.

    Article  CAS  Google Scholar 

  38. Hori T, Katafuchi T, Take S, Shimizu N . Neuroimmunomodulatory actions of hypothalamic interferon-α. Neuroimmunomodulation 1998; 5: 172–177.

    Article  CAS  Google Scholar 

  39. Mendoza-Fernandez V, Andrew RD, Barajas-Lopez C . Interferon-a inhibits long-term potentiation and unmasks a long-term depression in the rat hippocampus. Brain Res 2000; 885: 14–24.

    Article  CAS  Google Scholar 

  40. Muller M, Fontana A, Zbinden G, Gahwiler BH . Effects of interferons and hydrogen peroxide on CA3 pyramidal cells in rat hippocampal slice cultures. Brain Res 1993; 619: 157–162.

    Article  CAS  Google Scholar 

  41. Shakil AO, Di Bisceglie AM, Hoofnagle JH . Seizures during alpha interferon therapy. J Hepatol 1996; 24: 48–51.

    Article  CAS  Google Scholar 

  42. Campbell IL, Krucker T, Steffensen S, Akwa Y, Powell HC, Lane T et al. Structural and functional neuropathology in transgenic mice with CNS expression of IFN-a. Brain Res 1999; 835: 46–61.

    Article  CAS  Google Scholar 

  43. Ritchie KJ, Malakhov MP, Hetherington CJ, Zhou L, Little MT, Malakhova OA et al. Dysregulation of protein modification by ISG15 results in brain cell injury. Genes Dev 2002; 16: 2207–2212.

    Article  CAS  Google Scholar 

  44. Wong ML, Licinio J . Research and treatment approaches to depression. Nat Rev Neurosci 2001; 2: 343–351.

    Article  CAS  Google Scholar 

  45. Yolken RH, Torrey EF . Viruses, schizophrenia, and bipolar disorder. Clin Microbiol Rev 1995; 8: 131–145.

    Article  CAS  Google Scholar 

  46. Nakamura K, Xiu Y, Ohtsuji M, Sugita G, Abe M, Ohtsuji N et al. Genetic dissection of anxiety in autoimmune disease. Hum Mol Genet 2003; 12: 1079–1086.

    Article  CAS  Google Scholar 

  47. Bannerman DM, Rawlins JN, McHugh SB, Deacon RM, Yee BK, Bast T et al. Regional dissociations within the hippocampus – memory and anxiety. Neurosci Biobehav Rev 2004; 28: 273–283.

    Article  CAS  Google Scholar 

  48. Schutter DJ, van Honk J . The cerebellum on the rise in human emotion. Cerebellum 2005; 4: 290–294.

    Article  Google Scholar 

  49. Li Y, Srivastava KK, Platanias LC . Mechanisms of type I interferon signaling in normal and malignant cells. Arch Immunol Ther Exp (Warsz) 2004; 52: 156–163.

    CAS  Google Scholar 

  50. Uddin S, Fish EN, Sher DA, Gardziola C, White MF, Platanias LC . Activation of the phosphatidylinositol 3-kinase serine kinase by IFN-α. J Immunol 1997; 158: 2390–2397.

    CAS  PubMed  Google Scholar 

  51. Uddin S, Majchrzak B, Woodson J, Arunkumar P, Alsayed Y, Pine R et al. Activation of the p38 mitogen-activated protein kinase by type I interferons. J Biol Chem 1999; 274: 30127–30131.

    Article  CAS  Google Scholar 

  52. Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, Dighe AS et al. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 1996; 84: 431–442.

    Article  CAS  Google Scholar 

  53. Durbin JE, Hackenmiller R, Simon MC, Levy DE . Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 1996; 84: 443–450.

    Article  CAS  Google Scholar 

  54. Makino M, Kitano Y, Komiyama C, Takasuna K . Human interferon-a increases immobility in the forced swimming test in rats. Psychopharmacology 2000; 148: 106–110.

    Article  CAS  Google Scholar 

  55. De La Garza II R, Asnis GM, Pedrosa E, Stearns C, Migdal AL, Reinus JF et al. Recombinant human interferon-α does not alter reward behavior, or neuroimmune and neuroendocrine activation in rats. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 781–792.

    Article  CAS  Google Scholar 

  56. De La Garza II R, Asnis GM . The non-steroidal anti-inflammatory drug diclofenac sodium attenuates IFN-α induced alterations to monoamine turnover in prefrontal cortex and hippocampus. Brain Res 2003; 977: 70–79.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr Jerry Q Feng (Department of Oral Biology, UMKC) for his help with the digital image capture. We also thank Drs Willard Morrow (Department of Basic Medical Sciences, UMKC) and Orisa J Igwe (Department of Pharmacology, UMKC) for their comments on the manuscript. This work was supported by NIH grants MH 69524 to JW and MH 62231 and MH 62261 to ILC.

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  1. Department of Pharmacology, University of Missouri-Kansas City, Kansas City, MO, USA

    J Wang & H Zhang

  2. School of Molecular and Microbial Biosciences, University of Sydney, Sydney, NSW, Australia

    I L Campbell

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Correspondence to J Wang.

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Wang, J., Campbell, I. & Zhang, H. Systemic interferon-α regulates interferon-stimulated genes in the central nervous system. Mol Psychiatry 13, 293–301 (2008). https://doi.org/10.1038/sj.mp.4002013

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