title: Disturbance of tumor necrosis factor alpha-mediated beta interferon signaling in cervical carcinoma cells.
abstract: In the present study we show that malignant human papillomavirus (HPV)-positive cells lost their ability to synthesize endogenous beta interferon (IFN-beta) upon tumor necrosis factor alpha (TNF-alpha) treatment. IFN-beta 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-beta 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-beta, IFN-alpha, or IFN-gamma was added exogenously. This indicates that only the cross talk between TNF-alpha and the IFN-beta pathways, and not IFN-alpha/beta 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 (ISGF3gamma) emerged as key regulatory molecules in the differential IFN-beta 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-beta 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-beta nor antiviral activity could be restored.
authors.affiliation: Forschungsschwerpunkt Angewandte Tumorvirologie, Abteilung Tumorvirus-Immunologie, Deutsches Krebsforschungszentrum, Heidelberg, Federal Republic of Germany.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Bachmann
authors.forename: Brigitte
authors.initials: B
authors.lastname: Hanke
authors.forename: Rainer
authors.initials: R
authors.lastname: Zawatzky
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Soto
authors.forename: Jan
authors.initials: J
authors.lastname: van Riggelen
authors.forename: Harald
authors.initials: H
authors.lastname: zur Hausen
authors.forename: Frank
authors.initials: F
authors.lastname: Rösl
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006822:Hybrid Cells; D016899:Interferon-beta / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D030361:Papillomavirus Infections / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000821:virology
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta