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Antimicrobial Agents and Chemotherapy, June 2003, p. 1912-1921, Vol. 47, No. 6
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.6.1912-1921.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Ribavirin and Alpha Interferon Enhance Death Receptor-Mediated Apoptosis and Caspase Activation in Human Hepatoma Cells

Stephan F. Schlosser,1* Markus Schuler,2 Christoph P. Berg,2 Kirsten Lauber,2 Klaus Schulze-Osthoff,3 Friedrich Wilhelm Schmahl,1 and Sebastian Wesselborg2

Department of Occupational and Social Medicine,1 and Department of Internal Medicine I,2 University of Tübingen, Tübingen, and Department of Molecular Medicine, University of Düsseldorf, Düsseldorf, Germany3

Received 11 July 2002/ Returned for modification 3 October 2002/ Accepted 26 February 2003

The molecular mechanisms underlying the clinical effects of alpha interferon (IFN) and ribavirin are not understood. Elimination of infected cells occurs in part by cytotoxic T lymphocytes (CTLs) expressing CD95 ligand and thereby attacking target cells which are positive for the death receptor CD95. Since many viruses have evolved mechanisms to inhibit apoptosis, the opposite, namely, promotion of apoptosis, could be a strategy to strengthen the host antiviral response. In the present study, we have asked whether the antiviral substances IFN and ribavirin could support CD95-mediated apoptosis by interfering with the activation of caspases, a family of proteases known for their essential role in apoptosis. HepG2 cells, stimulated with the agonistic anti-CD95 antibody, served as a minimal model to mimic the CD95 stimulation ocurring during a CTL attack of target cells in vivo. Apoptosis was quantitated by flow cytometric detection of hypodiploid nuclei. Caspase activity was measured by cytofluorometry, immunocytochemistry, and immunoblot analysis. IFN and ribavirin sensitized HepG2 cells for CD95-mediated apoptosis. This effect was correlated with an increase in CD95-mediated caspase activation and enhanced cleavage of the caspase substrate poly(ADP-ribose) polymerase. Furthermore, the positive effect on CD95-mediated caspase activation by IFN and ribavirin was confirmed by immunocytochemistry for activated caspase-3 and by immunoblot detection of activated caspase-3, caspase-7, and caspase-8. Our data demonstrate that the antiviral substances IFN and ribavirin are able to sensitize for CD95-mediated apoptosis. IFN and ribavirin also enhance CD95-mediated caspase activation, which might in part be responsible for the apoptosis-promoting effect of these antiviral compounds.

* Corresponding author. Mailing address: Department of Occupational and Social Medicine, Eberhard-Karls-University, Wilhelmstr. 27, D-72074 Tübingen, Germany. Phone: 49-7071-29-80151 or 82082. Fax: 49-7071-29-4362. E-mail: stephan.f.schlosser{at}uni-tuebingen.de.

Antimicrobial Agents and Chemotherapy, June 2003, p. 1912-1921, Vol. 47, No. 6
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.6.1912-1921.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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