Direct Induction of Interferon-γ– and Interferon-α/β–Inducible Genes by Double-Stranded RNA

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Abstract
Using Northern analysis, we here show that the inducibility by double-stranded (ds) RNA of interferon-α/β -inducible genes is not restricted to a few genes but extends to all the genes known to be stimulated by IFN type I in fibroblasts. Moreover, we show that some genes, preferentially regulated by IFN-γ, are also activated by dsRNA. We present a series of arguments demonstrating that the induction by dsRNA is not mediated by IFN. In addition to the fact that this induction occurs in the presence of cycloheximide and/or anti-IFN-α/β antibodies in fibroblasts, we observed that, in IFN-resistant Daudi cells, ISG15 and IP-10 genes which are not induced by IFN-β, are still inducible by dsRNA. dsRNA is also still active on 2-5 AS and ISG15 genes in cells carrying homozygous deletions of IFN α/β genes. Actinomycin D experiments and nuclear in vitro elongation assays reveal that the induction by dsRNA involves, as its early step, a transcriptional event. This induction was found not to require protein synthesis, suggesting that activation of preexisting cellular factors is involved. The opposite inducibility by dsRNA of IFN-β and 2′,5′-oligoadenylate (2-5A) synthetase genes in serum-deprived fibroblasts indicates that pathways of induction by dsRNA of these two genes are not identical. Inhibition by 2-aminopurine of the induction of IFN-inducible mRNAs by IFN-β or dsRNA suggests the participation of a protein kinase in their mechanism of action.