Determinants of cytokine induction by small interfering RNA in human peripheral blood mononuclear cells

Maryam Zamanian-Daryoush, Joao Trindade Marques, Michael Paul Marie Gantier, Mark A Behlke, Matthias John, Patricia Rayman, James Finke, Bryan Raymond George Williams

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45 Citations (Scopus)

Abstract

Synthetic small interfering RNAs (siRNAs) can trigger a strong innate immune response in mammalian cells. This nonspecific side effect may hinder the application of siRNAs as tools in gene silencing. Chemically synthesized siRNAs, including traditional 19-mers with 2-nt 3 overhangs, longer duplexes with blunt or 3 overhangs, and asymmetric duplexes with a blunt end and a 2-nt 3 overhang, can evoke strong dose-dependent interferon-alpha (IFN-alpha) and tumor necrosis factor-alpha (TNF-alpha) release in human peripheral blood mononuclear cells (PBMCs). This response is independent of retinoic acid-inducible gene I but may involve endosomal toll-like receptors (TLRs). The immunostimulatory effect of the siRNAs is directly related to either or both of the strands of the duplex in a sequence-dependent manner. However, although some single-stranded RNAs and siRNAs potently evoked both IFN-alpha and TNF-alpha induction, these responses were not always coupled. In accordance with this, specific chemical modifications differentially altered cytokine production, suggesting recruitment of different TLRs in a sequence-dependent manner.
Original languageEnglish
Pages (from-to)221 - 233
Number of pages13
JournalJournal of Interferon and Cytokine Research
Volume28
Issue number4
Publication statusPublished - 2008

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