Nature Cell Biology
5, 834 - 839 (2003)
Published online: 24 August 2003; | doi:10.1038/ncb1038
Activation of the interferon system by short-interfering RNAsCarol A. Sledz1, 2, Michelle Holko1, 3, Michael J. de Veer1, Robert H. Silverman1, 2
& Bryan R.G. Williams1, 2, 31
Department of Cancer Biology, Lerner Research Institute, NB40, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195 USA. 2
Molecular Virology Program, Case Western Reserve University, Cleveland, OH 44106, USA. 3
Department of Genetics, Case Western Reserve University, Cleveland, OH 44106, USA.
Correspondence should be addressed to Bryan R.G. Williams williab@ccf.orgRNA interference (RNAi) is a powerful tool used to manipulate gene expression or determine gene function1,
2. One technique of expressing the short double-stranded (ds) RNA intermediates required for interference in mammalian systems is the introduction of short-interfering (si) RNAs3,
4,
5,
6. Although RNAi strategies are reliant on a high degree of specificity, little attention has been given to the potential non-specific effects that might be induced. Here, we found that transfection of siRNAs results in interferon (IFN)-mediated activation of the Jak−Stat pathway and global upregulation of IFN-stimulated genes. This effect is mediated by the dsRNA-dependent protein kinase, PKR, which is activated by 21-base-pair (bp) siRNAs and required for upregulation of IFN- in response to siRNAs. In addition, we show by using cell lines deficient in specific components mediating IFN action that the RNAi mechanism itself is independent of the interferon system. Thus, siRNAs have broad and complicating effects beyond the selective silencing of target genes when introduced into cells. This is of critical importance, as siRNAs are currently being explored for their potential therapeutic use7,
8.
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