| Immunostimulatory Potential of Silencing RNAs Can Be Mediated by a Non-Uridine-Rich Toll-Like Receptor 7 Motif. | |
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MedLine Citation:
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PMID: 21749297 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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Microbial infections trigger a multiplicity of responses in the host via innate immune sensors, including the Toll-like receptors (TLRs). TLR7 and TLR8, located in endosomes, detect pathogen-derived RNA, which can be mimicked by synthetic single-stranded oligoribonucleotides (ORNs). Detailed analysis of the immunostimulatory properties of numerous silencing RNAs (siRNAs) revealed that almost all tested siRNAs with a phosphodiester backbone actively stimulated cytokine production in human peripheral blood immune cells, but not all of them did contain previously described guanosine/uridine TLR7 or adenosine/uridine TLR8 motifs. By analysis of sequence variants of these siRNAs (as single- or double-strands), we were able to identify a new immunostimulatory, non-uridine-rich TLR7 motif that is present in many published siRNAs. Interestingly, the activity of this motif is dependent on the backbone chemistry. Phosphorothioate ORNs containing the motif did not stimulate immune activation, whereas phosphodiester ORNs of the same sequence induced a strong TLR7-biased immune response with high amounts of interferon-alpha. Using TLR7- and Myd88-deficient mice, we demonstrated that stimulation by ORNs containing this motif was TLR7 dependent. Our findings are of therapeutic relevance as this motif is present in many siRNA sequences and will to contribute to the immunostimulatory properties of unmodified siRNAs. |
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Authors:
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Marion Jurk; Ghania Chikh; Bettina Schulte; Andrea Kritzler; Denise Richardt-Pargmann; Catherine Lampron; Rachel Luu; Arthur M Krieg; Alain P Vicari; Jörg Vollmer |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Nucleic acid therapeutics Volume: 21 ISSN: 2159-3345 ISO Abbreviation: Nucl Acid Ther Publication Date: 2011 Jun |
Date Detail:
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Created Date: 2011-07-13 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101562758 Medline TA: Nucl Acid Ther Country: United States |
Other Details:
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Languages: eng Pagination: 201-14 Citation Subset: IM |
Affiliation:
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1 Pfizer Oligonucleotide Therapeutics Unit (OTU), Coley Pharmaceutical GmbH , Düsseldorf, Germany . |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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