Nature Medicine11, 263 - 270 (2005)
Published online: 20 February 2005; | doi:10.1038/nm1191
Sequence-specific potent induction of IFN- by short interfering RNA in plasmacytoid dendritic cells through TLR7
Veit Hornung1, Margit Guenthner-Biller1, Carole Bourquin1, Andrea Ablasser1, Martin Schlee2, Satoshi Uematsu4, Anne Noronha3, Muthiah Manoharan3, Shizuo Akira4, Antonin de Fougerolles3, Stefan Endres1
& Gunther Hartmann1
1
Department of Internal Medicine, Division of Clinical Pharmacology, Ludwig-Maximilians-University of Munich, Ziemssenstr. 1, 80336 München, Germany.
2
GSF National Research Centre for Environment and Health, Institute of Clinical Molecular Biology and Tumor Genetics, Marchioninistr. 25, 81377 München, Germany.
Short interfering RNA (siRNA) is used in RNA interference technology to avoid non-target-related induction of type I interferon (IFN) typical for long double-stranded RNA. Here we show that in plasmacytoid dendritic cells (PDC), an immune cell subset specialized in the detection of viral nucleic acids and production of type I IFN, some siRNA sequences, independent of their GU content, are potent stimuli of IFN- production. Localization of the immunostimulatory motif on the sense strand of a potent IFN--inducing siRNA allowed dissection of immunostimulation and target silencing. Injection into mice of immunostimulatory siRNA, when complexed with cationic liposomes, induced systemic immune responses in the same range as the TLR9 ligand CpG, including IFN- in serum and activation of T cells and dendritic cells in spleen. Immunostimulation by siRNA was absent in TLR7-deficient mice. Thus sequence-specific TLR7-dependent immune recognition in PDC needs to be considered as an additional biological activity of siRNA, which then should be termed immunostimulatory RNA (isRNA).
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