Skip to main content

Advertisement

SpringerLink
Log in

Effect of the N-butanoyl glutathione (GSH) derivative and acyclovir on HSV-1 replication and Th1 cytokine expression in human macrophages

  • Rapid Communication
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract

Macrophages are an important defense against in vivo herpes simplex virus (HSV) infection by early cytokine secretion; however, they can be infected by HSV-1 and they may be compromised in their ability to produce cytokines. In this paper, we studied the expression of two Th1 cytokines, interleukin (IL)-12 and IL-27, upon HSV-1 infection of human macrophages, and how it is regulated by treatment with two antiviral drugs exerting their anti-HSV-1 activity through different mechanisms of action. We found that infection does not alter intra-macrophage thiol content, while it induces mRNA expression of IL-12 p35 and IL-12 p40 as well as of IL-27 p28 and IL-27 EBI3, as revealed by RT-PCR. The increased expression of mRNA is accompanied by increased production of IL-12 p40 and IL-27 p28 protein, as detected in the culture supernatants by ELISA. The two antiviral drugs tested were acyclovir (ACV), commonly used to treat herpes virus infections, and an N-butanoyl glutathione (GSH) derivative, GSH-C4. While ACV inhibits viral DNA polymerase, GSH-C4 inhibits virus replication by interfering with protein folding and maturation of viral particles. Indeed, GSH-C4, altering the intracellular redox state, may modulate the Th1/Th2 balance favoring Th1-type response. Our data show that both drugs inhibit HSV-1 replication in macrophages, without significantly affecting cytokine mRNA levels. Nonetheless, lower levels of IL-12 p40 and IL-27 p28 proteins were found in the supernatants of macrophages treated with either GSH-C4 or ACV, likely as an indirect consequence of inhibited HSV-1 replication.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Roizman B, Knipe D, Whitley R (2007) Herpes simplex viruses. In: Knipe DMHP (ed) Fields’ virology, 5th edn. Lippincott Williams & Wilkins, Philadelphia, pp 2501–2601

    Google Scholar 

  2. Whitley RJ, Roizman B (2001) Herpes simplex virus infections. Lancet 357:1513–1518

    Article  CAS  PubMed  Google Scholar 

  3. Kodukula P, Liu T, van Rooijen N, Jager MJ, Hendricks RL (1999) Macrophage control of Herpes simplex virus type 1 replication in the peripheral nervous system. J Immunol 162:2895–2905

    CAS  PubMed  Google Scholar 

  4. Milligan GN, Bernstein DI (1997) Interferon-γ enhances resolution of Herpes simplex virus type 2 infection of the murine genital tract. Virology 229:259–268

    Article  CAS  PubMed  Google Scholar 

  5. Scieux C (1997) Herpes simplex virus and macrophages. Pathol Biol 45:159–164

    CAS  PubMed  Google Scholar 

  6. Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3:133–146

    Article  CAS  PubMed  Google Scholar 

  7. Batten M, Ghilardi N (2007) The biology and therapeutic potential of interleukin 27. J Biol Med 85:661–672

    CAS  Google Scholar 

  8. Kumaraguru U, Rouse BT (2002) The IL-12 response to herpes simplex virus is mainly a paracrine response of reactive inflammatory cells. J Leukoc Biol 72:564–570

    CAS  PubMed  Google Scholar 

  9. Mertz GJ (1990) Herpes virus simplex. In: Galasso GJ, Whitley RJ, Merigan TC (eds) Antiviral agents and viral disease of man. Raven Press, New York, pp 265–300

    Google Scholar 

  10. Fraternale A, Paoletti MF, Casabianca A, Nencioni L, Garaci E, Palamara AT, Magnani M (2009) GSH and analogs in antiviral therapy. Mol Aspects Med 30:99–110

    Article  CAS  PubMed  Google Scholar 

  11. Murata Y, Shimamura T, Hamuro J (2002) The polarization of T(h)1 T(h)2 balance is dependent on the intracellular thiol redox status of macrophages due to the distinctive cytokine production. Int Immunol 14:201–212

    Article  CAS  PubMed  Google Scholar 

  12. Koike Y, Hisada T, Utsugi M, Ishizuka T, Shimizu Y et al (2007) Glutathione redox regulates airway hyperresponsiveness and airway inflammation in mice. Am J Respir Cell Mol Biol 37:322–329

    Article  CAS  PubMed  Google Scholar 

  13. Fraternale A, Paoletti MF, Dominici S et al (2010) The increase in intra-macrophage thiols induced by new pro-GSH molecules directs the Th1 skewing in ovalbumin immunized mice. Vaccine 28:7676–7682

    Article  CAS  PubMed  Google Scholar 

  14. Fraternale A, Paoletti MF, Dominici S et al (2011) Modulation of Th1/Th2 immune responses to HIV-1 Tat by new pro-GSH molecules. Vaccine 29:6823–6829

    Article  CAS  PubMed  Google Scholar 

  15. Brandi G, Schiavano GF, Balestra E, Tavazzi B, Perno C-F, Magnani M (2001) The potency of acyclovir can be markedly different in different cell types. Life Sci 69:1285–1290

    Article  CAS  Google Scholar 

  16. Dobashi K, Aihara M, Araki T et al (2001) Regulation of LPS induced IL-12 production by IFN-gamma and IL-4 through intracellular glutathione status in human alveolar macrophages. Clin Exp Immunol 124:290–296

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Beutler E (1984) Red cell metabolism. In: Grune Stratton (ed) A manual of biochemical methods. USA Press, New York, pp 131–133

    Google Scholar 

  18. Palamara AT, Brandi G, Rossi L et al (2004) New synthetic glutathione derivatives with increased antiviral activities. Antivir Chem Chemother 15:11–19

    Google Scholar 

  19. D’Andrea A, Rengaraju M, Valiante NM et al (1992) Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J Exp Med 176:1387–1398

    Article  PubMed  Google Scholar 

  20. Frank GM, Divito SJ, Maker DM, Xu M, Hendricks RL (2010) A novel p40-independent function of IL-12p35 is required for progression and maintenance of herpes stromal keratitis. Invest Ophthalmol Vis Sci 51:3591–3598

    Article  PubMed Central  PubMed  Google Scholar 

  21. Schnurr M, Toy T, Shin A, Wagner M, Cebon J, Maraskvsky E (2005) Extracellular nucleotide signalling by P2 receptors inhibits IL-12 and enhances IL-23 expression in human dendritic cells: a novel role fro the cAMP pathway. Blood 105:1582–1589

    Article  CAS  PubMed  Google Scholar 

  22. Sareneva T, Matikainen S, Kurimoto M, Julkunen I (1998) Influenza A virus-induced IFN-alpha/beta and IL-18 synergistically enhance IFN-gamma gene expression in human T cells. J Immunol 160:6032–6038

    CAS  PubMed  Google Scholar 

  23. Mazzeo D, Sacco S, Di Lucia P et al (2002) Thiol antioxidants inhibit the formation of the interleukin-12 heterodimer: a novel mechanism for the inhibition of IL-12 production. Cytokine 17:285–293

    Article  CAS  PubMed  Google Scholar 

  24. Alam K, Ghousunnissa S, Nair S, Valluri VL, Mukhopadhyay S (2010) Glutathione-redox balance regulates c-rel-driven IL-12 production in macrophages: possible implications in antituberculosis immunotherapy. J Immunol 184:2918–2929

    Article  CAS  PubMed  Google Scholar 

  25. Patel A, Hanson J, McLean T et al (1998) Herpes simplex type 1 induction of persistent NF-kB nuclear translocation increases the efficiency of virus replication. Virology 247:212–222

    Article  CAS  PubMed  Google Scholar 

  26. Murphy TL, Cleveland MG, Kulesza P, Magram J, Murphy KM (1995) Regulation of interleukin 12 p40 expression through an NF-kB half-site. Mol Cell Biol 17:5258–5267

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, Via Saffi, 2, 61029, Urbino, PU, Italy

    Alessandra Fraternale, Giuditta Fiorella Schiavano, Maria Filomena Paoletti, Linda Palma, Mauro Magnani & Giorgio Brandi

Authors
  1. Alessandra Fraternale
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giuditta Fiorella Schiavano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Filomena Paoletti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Linda Palma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mauro Magnani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giorgio Brandi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alessandra Fraternale.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fraternale, A., Schiavano, G.F., Paoletti, M.F. et al. Effect of the N-butanoyl glutathione (GSH) derivative and acyclovir on HSV-1 replication and Th1 cytokine expression in human macrophages. Med Microbiol Immunol 203, 283–289 (2014). https://doi.org/10.1007/s00430-014-0335-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-014-0335-4

Keywords

Search

Navigation