TUMOR NECROSIS FACTOR ACTS SYNERGISTICALLY WITH AUTOCRINE INTERFERON-BETA AND INCREASES INTERFERON-BETA MESSENGER-RNA LEVELS IN HUMAN-FIBROBLASTS

Abstract

Medium of untreated human FS-4 foreskin fibroblasts contained a factor which, upon the addition of exogenous tumor necrosis factor (TNF), inhibited encephalomyocarditis virus replication when neither medium alone nor TNF alone were effective. This antiviral activity was abolished by a monoclonal antibody to human interferon (IFN)-.beta., suggesting that the active component in the medium from untreated FS-4 cells was IFN-.beta., present at subeffective concentrations. In addition, we show that untreated FS-4 cells contain IFN-.beta. mRNA, demonstrable by the highly sensitive polymerase chain reaction after reverse transcription. Treatment of FS-4 cells with TNF produced an approximately 16-fold increase in the steady-state level of IFN-.beta. mRNA. Our results support the conclusion that autocrine IFN-.beta. is secreted by untreated normal fibroblasts and that TNF can enhance the production of autocrine IFN-.beta. by increasing the level of IFN-.beta. mRNA. Our study also demonstrates that subeffective concentrations of autocrine IFN-.beta., which escape detection in conventional assays, are sufficient to produce a strong synergistic action with TNF.