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Journal of Virology, January 2002, p. 280-291, Vol. 76, No. 1
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.1.280-291.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Disturbance of Tumor Necrosis Factor Alpha-Mediated Beta Interferon Signaling in Cervical Carcinoma Cells

Anastasia Bachmann, Brigitte Hanke, Rainer Zawatzky, Ubaldo Soto, Jan van Riggelen, Harald zur Hausen, and Frank Rösl*

Forschungsschwerpunkt Angewandte Tumorvirologie, Abteilung Tumorvirus-Immunologie, Deutsches Krebsforschungszentrum, Heidelberg, Federal Republic of Germany

Received 3 July 2001/ Accepted 28 September 2001

In the present study we show that malignant human papillomavirus (HPV)-positive cells lost their ability to synthesize endogenous beta interferon (IFN-ß) upon tumor necrosis factor alpha (TNF-{alpha}) treatment. IFN-ß transcription, however, was reinducible in nonmalignant HPV-positive cells, which was confirmed in functional protection assays against encephalomyocarditis virus or vesicular stomatitis virus infections. Addition of neutralizing antibodies against IFN-ß blocked the antiviral effect, excluding the possibility that other IFN types were involved. Conversely, both malignant and immortalized cells could be protected against viral cytolysis when either IFN-ß, IFN-{alpha}, or IFN-{gamma} was added exogenously. This indicates that only the cross talk between TNF-{alpha} and the IFN-ß pathways, and not IFN-{alpha}/ß and IFN-{gamma} signaling in general, is perturbed in cervical carcinoma cells. Notably, full virus protection was restricted exclusively to nonmalignant cells, indicating that the antiviral effect correlates with the growth-inhibitory and virus-suppressive properties of TNF-{alpha}. The IFN-regulatory factors IRF-1 and p48 (ISGF3{gamma}) emerged as key regulatory molecules in the differential IFN-ß response, since their transcription was either absent or only inefficiently enhanced in tumorigenic cells upon treatment with TNF-{alpha}. Inducibility of both genes, however, became reestablished in cervical carcinoma cells, which were complemented to nontumorigenicity after somatic cell hybridization. Complementation was paralleled by the entire reconstitution of cytokine-mediated IFN-ß expression and the ability of TNF-{alpha} to exert an antiviral state. In contrast, under conditions where tumor suppression was not accomplished upon somatic cell hybridization, neither expression of IRF-1, p48, and IFN-ß nor antiviral activity could be restored.

* Corresponding author. Mailing address: Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, 69120 Heidelberg, Federal Republic of Germany. Phone: 49-6221-42-4900. Fax: 49-6221-42-4902. E-mail: F.Roesl{at}DKFZ.de.

Journal of Virology, January 2002, p. 280-291, Vol. 76, No. 1
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.1.280-291.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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