Interferon Defense System Responds to siRNA

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Science's STKE  09 Sep 2003:
Vol. 2003, Issue 199, pp. tw343-TW343
DOI: 10.1126/stke.2003.199.tw343

The use of small-interfering RNAs (siRNAs) to inhibit gene expression in mammalian cells is a strategy now widely used to determine gene function. Its potential therapeutic value is based on the fact that these short, 21-base pair, double-stranded RNAs were thought not to activate the interferon defense system of mammalian cells. However, Sledz et al. report that siRNAs can activate the interferon system and, thus, may have more broad effects than previously suspected. The interferon system is induced when double-stranded RNA, produced during viral infection, activates signaling cascades that not only turn on the expression of interferon and interferon-stimulated genes but also activate PKR, a protein kinase that arrests protein synthesis. The authors examined 850 putative interferon-stimulated genes (ISGs) and observed that 52 were induced in a mammalian cell line when different siRNAs [such as siRNA that targets glyceraldehyde-3-phosphate dehydrogenase (GAPDH)] were tested. For example, cells treated with lamin-specific siRNA showed activation of Stat1 expression, a signaling protein that is expressed in response to interferons. This response was not observed in cells lacking interferons. This nonspecific effect also depended on expression of PKR and other components of the interferon system including Jak1. Induction of ISG expression in response to siRNA was dose-dependent in some cases. The study suggests cautious interpretation of data based on the application of siRNA and consideration of possible side effects if used in the clinic.

C. A. Sledz, M. Holko, M. J. de Veer, G. H. Silverman, B. R. G. Williams, Activation of the interferon system by short-interfering RNAs. Nat. Cell Biol. 5, 834-839 (2003). [Online Journal]

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