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

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.