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Influence of neopterin and 7,8-dihydroneopterin on the replication of Coxsackie type B5 and influenza A viruses

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Abstract

Pteridine derivatives neopterin and 7,8-dihydroneopterin are produced by human macrophages and dendritic cells upon stimulation with interferon-γ (IFN-γ) and therefore become detectable in increased amounts in humans during cell-mediated (Th1-type) immune response. Compounds produced upon influence of cytokine IFN-γ often exert antiproliferative and antiviral activity. The aim of this study was to investigate the effect of neopterin and 7,8-dihydroneopterin on the replication of Coxsackie type B5 and influenza A viruses. The changes in the replication of these viruses were evaluated by the degree of cytopathic effect and their ability to form plaques in Coxsackie B5-infected human larynx carcinoma epithelial (Hep-2) cells and in influenza A-infected canine kidney epithelial cells (MDCK). Potential toxicity of neopterin and 7,8-dihydroneopterin was estimated by the incorporation of 3H-thymidine and 3H-uridine into Hep-2 and MDCK cells. Whereas 30 nmol/l neopterin delayed the development of the cytopathic effect of Coxsackie B5 virus in Hep-2 cells (P < 0.01), 7,8-dihydroneopterin did not have any essential influence at any of the concentrations tested between 10 nmol/l and 1,000 μmol/l. However, 100–1,500 μmol/l 7,8-dihydroneopterin significantly suppressed the propagation of influenza A virus. Neopterin and 7,8-dihydroneopterin were practically nontoxic for Hep-2 and MDCK cells even at high μM concentration. Results suggest that the increased production of neopterin derivatives by activated macrophages and dendritic cells may represent part of the antiviral armature induced by IFN-γ. The mechanisms of the inhibitory effects of neopterin and 7,8-dihydroneopterin on virus replication apparently are different.

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References

  1. Schroder K, Hertzog PJ, Ravasi T, Hume DA (2004) Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 75:163–189

    Article  PubMed  CAS  Google Scholar 

  2. Murr C, Widner B, Wirleitner B, Fuchs D (2002) Neopterin as a marker for immune system activation. Curr Drug Metabol 3:175–187

    Article  CAS  Google Scholar 

  3. Hamerlinck FF (1999) Neopterin: a review. Exp Dermatol 8:167–176

    Article  PubMed  CAS  Google Scholar 

  4. Fuchs D, Milstien S, Kraemer A, Reibnegger G, Werner ER, Goedert JJ, Kaufman S, Wachter H (1989) Urinary neopterin concentrations vs. total neopterins for clinical utility. Clin Chem 35:2305–2307

    PubMed  CAS  Google Scholar 

  5. Weiss G, Glaser K, Kronberger P, Ambach E, Fuchs D, Bodner E, Wachter H (1992) Distinct distributions of D-erythro-neopterin in arteries and veins and its recovery by an enterohepatic circulation. Biol Chem Hoppe-Seyler 373:289–294

    PubMed  CAS  Google Scholar 

  6. Huber C, Batchelor JR, Fuchs D, Hausen A, Lang A, Niederwieser D, Reibnegger G, Swetly P, Troppmair J, Wachter H (1984) Immune response-associated production of neopterin: release from macrophages primarily under control of interferon-gamma. J Exp Med 160:310–316

    Article  PubMed  CAS  Google Scholar 

  7. Wirleitner B, Reider D, Ebner S, Böck G, Widner B, Jaeger M, Schennach H, Romani N, Fuchs D (2002) Monocyte-derived dendritic cells release neopterin. J Leukoc Biol 72:1148–1153

    PubMed  CAS  Google Scholar 

  8. Schennach H, Hessenberger G, Mayersbach P, Schoenitzer D, Fuchs D (2002) Acute cytomegalovirus infections in blood donors are indicated by increased serum neopterin concentrations. Med Microbiol Immunol 191:115–118

    Article  PubMed  CAS  Google Scholar 

  9. Weiss G, Fuchs D, Hausen A, Reibnegger G,Werner ER, Werner-Felmayer G, Semenitz E, Dierich MP, Wachter H (1993) Neopterin modulates toxicity mediated by reactive oxygen and chloride species. FEBS Lett 321:89–92

    Article  PubMed  CAS  Google Scholar 

  10. Oettl K, Reibnegger G (2002) Pteridine derivatives as modulators of oxidative stress. Curr Drug Metabol 3:203–209

    Article  CAS  Google Scholar 

  11. Hoffmann G, Wirleitner B, Fuchs D (2003) Potential role of immune system activation associated production of neopterin derivatives in humans. Inflam Res 52:313–321

    Article  CAS  Google Scholar 

  12. Hoffmann G, Schobersberger W, Frede S, Pelzer L, Fandrey J, Wachter H, Fuchs D, Grote J (1996) Neopterin activates transcription factor nuclear factor-kB in vascular smooth muscle cells. FEBS Lett 391:181–184

    Article  PubMed  CAS  Google Scholar 

  13. Schobersberger W, Hoffmann G, Grote J, Wachter H, Fuchs D (1995) Induction of inducible nitric oxide synthase expression by neopterin in vascular smooth muscle cells. FEBS Lett 377:461–464

    Article  PubMed  CAS  Google Scholar 

  14. Baier-Bitterlich G, Fuchs D, Murr C, Reibnegger G, Werner-Felmayer G, Sgonc R, Böck G, Dierich M, Wachter H (1995) Effect of neopterin and 7,8-dihydroneopterin on tumor necrosis factor-α induced programmed cell death. FEBS Lett 364:234–238

    Article  PubMed  CAS  Google Scholar 

  15. Hoffmann G, Kenn S, Wirleitner B, Deetjen C, Frede S, Smolny M, Rieder J, Fuchs D, Baier-Bitterlich G, Schobersberger W (1998) Neopterin induces nitric oxide-dependent apoptosis in rat vascular smooth muscle cells. Immunobiology 199:63–73

    PubMed  CAS  Google Scholar 

  16. Baier-Bitterlich G, Fuchs D, Zangerle R, Baeuerle P, Werner E, Fresser F, Überall F, Baier G, Wachter H (1997) Trans-activation of the HIV type I promoter by 7,8-dihydroneopterin in vitro. AIDS Res Hum Retroviruses 13:173–178

    Article  PubMed  CAS  Google Scholar 

  17. Baier-Bitterlich G, Baier G, Fuchs D, Boeck G, Hausen A, Utermann G, Pavelka M, Wachter H (1996) Role of 7,8-dihydroneopterin in T-cell apoptosis and HTLV-I transcription in vitro. Oncogene 13:2281–2285

    PubMed  CAS  Google Scholar 

  18. Murr C, Baier-Bitterlich G, Fuchs D, Werner ER, Esterbauer H Pfleiderer-W, Wachter H (1996) Effects of neopterin-derivatives on H2O2-induced luminol chemiluminescence: mechanistic aspects. Free Radic Biol Med 21:449–456

    Article  PubMed  CAS  Google Scholar 

  19. Wede I, Widner B, Fuchs D (1999) Neopterin derivatives modulate toxicity of reactive species on Escherichia coli. Free Rad Res 31:381–388

    Article  CAS  Google Scholar 

  20. Widner B, Baier-Bitterlich G, Wede I, Wirleitner B, Wachter H, Fuchs D (1998) Neopterin: indicator of oxidative stress and part of the cytotoxic armature of activated macrophages in humans. Pteridines 9:91–102

    CAS  Google Scholar 

  21. Mannick JB (1998) The antiviral role of nitric oxide. Free Radic Biol Med 25:693–697

    Google Scholar 

  22. Karupiah G, Xie QW, Buller RML, Nathan C, Duarte C, MacMicking JD (1998) Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase. Science 261:1612–1615

    Google Scholar 

  23. Croen K (1993) Evidence for an antiviral effect of nitric oxide: inhibition of herpes simplex type 1 replication. J Clin Investig 91:2446–2452

    Article  PubMed  CAS  Google Scholar 

  24. Lopez-Guerrero LA, Carraso L (1998) Effect of nitric oxide on poliovirus infection of two human cell lines. J Virol 72:2538–2540

    PubMed  CAS  Google Scholar 

  25. Zaragoza C, Ocampo CJ, Saura M, McMillan A, Lowenstein CJ (1997) Nitric oxide inhibition of Coxsackie virus replication in vitro. J Clin Investig 100:1760–1767

    PubMed  CAS  Google Scholar 

  26. Asano K, Chee CBE, Gaston B, Lilly CM, Gerard C, Drazen JM, Stamler JS (1994) Constitutive and inducible nitric oxide synthase gene expression, regulation and activity in human lung epithelial cells. Proc Natl Acad Sci USA 9l:10089–10093

    Article  Google Scholar 

  27. Rimmelzwaan GF, Baars MMJW, de Lijster P, Fouchies RAM, Osterhaus AD (1999) Inhibition of influenza virus replication by nitric oxide. J Virol 73:8880–8883

    PubMed  CAS  Google Scholar 

  28. Herpfer I, Greilberger J, Ledinski G, Widner B, Fuchs D, Juergens G (2002) Neopterin and 7,8-dihydroneopterin interfere with low density lipoprotein oxidation mediated by peroxynitrite and/or copper. Free Radic Res 36:509–520

    Article  PubMed  CAS  Google Scholar 

  29. Gieseg SP, Reibnegger G, Wachter H, Esterbauer H (1995) 7,8-Dihydroneopterin inhibits low density lipoprotein oxidation in vitro. Evidence that this macrophage secreted pteridine is an anti-oxidant. Free Radic Res 23:123–126

    PubMed  CAS  Google Scholar 

  30. Wirleitner B, Czaputa R, Oettl K, Böck G, Widner B, Reibnegger G, Baier G, Fuchs D, Baier-Bitterlich G (2001) Induction of apoptosis by 7,8-dihydroneopterin: involvement of radical formation. Immunobiology 203:629–641

    PubMed  CAS  Google Scholar 

  31. Oettl K, Wirleitner B, Baier-Bitterlich G, Grammer T, Fuchs D, Reibnegger G (1999) Formation of oxygen radicals is solutions of 7,8-dihydroneopterin. Biochem Biophys Res Commun 264:262–267

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

This work was supported by the government of the State of the Austrian Tyrol.

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Authors and Affiliations

  1. August Kirchenstein Institute of Microbiology and Virology, University of Latvia, Rātsupītes iela 1, 1067, Riga, Latvia

    Olga Bratslavska & Edvīns Miklaševičs

  2. P. Stradins Clinical University Hospital, Pilsoņu iela 13, 1002, Riga, Latvia

    Edvīns Miklaševičs & Agris Martinsons

  3. Faculty of Nursing Sciences, Rīga Stradiņš University, Dzirciema iela 16, 1007, Riga, Latvia

    Diana Platace

  4. Division of Biological Chemistry, Biocentre, Innsbruck Medical University, and Ludwig Boltzmann Institute of AIDS-Research, Fritz Pregl Strasse 3, Innsbruck, 6020, Austria

    Dietmar Fuchs

Authors
  1. Olga Bratslavska
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  2. Diana Platace
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  3. Edvīns Miklaševičs
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  4. Dietmar Fuchs
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  5. Agris Martinsons
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Correspondence to Dietmar Fuchs.

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Bratslavska, O., Platace, D., Miklaševičs, E. et al. Influence of neopterin and 7,8-dihydroneopterin on the replication of Coxsackie type B5 and influenza A viruses. Med Microbiol Immunol 196, 23–29 (2007). https://doi.org/10.1007/s00430-006-0025-y

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  • DOI: https://doi.org/10.1007/s00430-006-0025-y

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