Characterization of two independent mechanisms by which interferon-induced gene expression is down regulated.
Interferons (IFNs) induce the expression of a variety of cellular RNAs. Phorbol esters can inhibit IFN-induced expression of some of these RNAs, including ISG-54K. The actions of phorbol esters on IFN-activated ISG-54K transcription are cell specific and are reversed by inhibitors of protein synthesis. In those cell lines in which phorbol esters inhibit IFN-induced ISG-54K transcription, prolonged IFN exposure also induces a "desensitized state" such that further IFN exposure no longer induces ISG-54K expression. IFN-induced desensitization is also reversed by inhibitors of protein synthesis. Experiments are described to determine whether the mechanism by which phorbol esters inhibit IFN-activated ISG-54K expression is the same as the mechanism by which prolonged exposure to IFN makes cells refractory to further induction of ISG-54K expression. Cultured cells treated with 12-O-tetradecanoylphorbol 13-acetate (TPA) for 72 h are desensitized to phorbol esters such that further addition of phorbols does not inhibit IFN-induced ISG-54K expression. In both naive and TPA-desensitized human fibroblasts or WISH cells, prolonged IFN treatment induced a desensitized state that was reversible by cycloheximide. This observation suggests that the mechanisms by which prolonged IFN treatment and phorbol esters inhibit ISG-54K expression are independent.
Akai
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Laboratory of Cytokine Research, Center for Biologics Evaluation and Research, National Institutes of Health, Bethesda, Maryland 20892.
Larner
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AC
D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007700:Kinetics; D010703:Phorbol Esters / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D015347:RNA Probes; D016372:RNA, Antisense; D011994:Recombinant Proteins; D014158:Transcription, Genetic
D010703:Phorbol Esters; D011500:Protein Synthesis Inhibitors; D015347:RNA Probes; D016372:RNA, Antisense; D011994:Recombinant Proteins; D007371:Interferon-gamma