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

Abstract

Using Northern analysis, we here show that the inducibility by double-stranded (ds) RNA of interferon-alpha/beta-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-gamma, 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-alpha/beta antibodies in fibroblasts, we observed that, in IFN-resistant Daudi cells, ISG15 and IP-10 genes which are not induced by IFN-beta, are still inducible by dsRNA. dsRNA is also still active on 2-5 AS and ISG15 genes in cells carrying homozygous deletions of IFN alpha/beta 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-beta 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-beta or dsRNA suggests the participation of a protein kinase in their mechanism of action.

Survey of Transcript Expression in Rainbow Trout Leukocytes Reveals a Major Contribution of Interferon-Responsive Genes in the Early Response to a Rhabdovirus Infection

“…Indeed, it is noteworthy that interferon transcripts were rarely retrieved in global surveys of virus-induced genes. Although inductions that bypass interferon were described for several interferon-activated genes in mammals (21,35), and for vig-1 in rainbow trout (8), the hypothesis that the interferon pathway may have not been activated in our experiment is much less likely. Indeed, trout leukocyte primary cultures were shown to produce interferon when incubated with VHSV (40).…”

Identification and characterization of two homologues of interferon-stimulated gene ISG15 in crucian carp

“…It is well known that there is complex mechanism on induced expression of mammalian ISG15. Upon virus infection, expression of ISG15 is induced mainly through type I IFN signalling [32], while Poly I:C regulates transcription of ISG15 via type I IFN or in an IFN-independent fashion [33]. LPS is one of the Gram-negative bacterial cell surface molecules, and it may activate the ISGylation system via the TLR4 signalling pathway [32].…”

Enhanced Expression of Interferon-Regulated Genes in the Liver of Patients with Chronic Hepatitis C Virus Infection: Detection by Suppression-Subtractive Hybridization

“…However, direct measurements of IFN-␣-and IFN-␤-specific transcripts revealed no significant increase in either HBV-or HCV-infected individuals compared to the control group (unpublished data), possibly because the genes are activated by alternative pathways. At least for IFI-56K, MxA, and IP-10, there is substantial evidence on induction pathways by double-stranded RNA or viral infection that bypass interferons (16,17,29,51). These findings might have implications for therapeutic considerations.…”