Disturbance of tumor necrosis factor alpha-mediated beta interferon signaling in cervical carcinoma cells

A. Bachmann, B. Hanke, R. Zawatzky, U. Soto, J. Van Riggelen, H. Zur Hausen, F. Rösl

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24 Scopus citations

Abstract

In the present study we show that malignant human papillomavirus (HPV)-positive cells lost their ability to synthesize endogenous beta interferon (IFN-β) upon tumor necrosis factor alpha (TNF-α) treatment. IFN-β 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-β 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-β, IFN-α, or IFN-γ was added exogenously. This indicates that only the cross talk between TNF-α and the IFN-β pathways, and not IFN-α/β and IFN-γ 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-α. The IFN-regulatory factors IRF-1 and p48 (ISGF3γ) emerged as key regulatory molecules in the differential IFN-β response, since their transcription was either absent or only inefficiently enhanced in tumorigenic cells upon treatment with TNF-α. 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-β expression and the ability of TNF-α 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-β nor antiviral activity could be restored.

Original languageEnglish (US)
Pages (from-to)280-291
Number of pages12
JournalJournal of Virology
Volume76
Issue number1
DOIs
StatePublished - Jan 1 2002

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ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Bachmann, A., Hanke, B., Zawatzky, R., Soto, U., Van Riggelen, J., Zur Hausen, H., & Rösl, F. (2002). Disturbance of tumor necrosis factor alpha-mediated beta interferon signaling in cervical carcinoma cells. Journal of Virology, 76(1), 280-291. https://doi.org/10.1128/JVI.76.1.280-291.2002