RRC ID 1957
Author Okahira S, Nishikawa F, Nishikawa S, Akazawa T, Seya T, Matsumoto M.
Title Interferon-beta induction through toll-like receptor 3 depends on double-stranded RNA structure.
Journal DNA Cell Biol.
Abstract Type I interferons (IFN-alpha/beta) play an essential role in both innate and adaptive antiviral immune responses. IFN- beta is produced by fibroblasts and myeloid dendritic cells (DCs) upon viral infection or in response to doublestranded RNA (dsRNA). Several intracellular molecules having a dsRNA-binding motif such as dsRNA-dependent protein kinase recognize dsRNA in a sequence-independent manner and induce antiviral innate responses. Toll-like receptor (TLR) 3, a member of TLR family proteins, recognizes extracellular dsRNA and activates NF- kappaB and the IFN-beta promoter leading to the induction of IFN-beta production. Here we analyzed the dsRNA structure capable of inducing TLR3-mediated IFN-beta production using various synthetic RNA duplexes. In contrast to the recognition of dsRNA by intracellular molecules, TLR3 preferentially recognizes polyriboinocinic:polyribocytidylic acid (poly(I:C)) rather than synthetic virus-derived dsRNAs. 2'-O-methyl or 2'-fluoro modification of cytidylic acid abolished the IFN-beta-inducing ability of the poly(I:C) duplex, and these modified dsRNAs inhibited poly(I:C)-induced TLR3-mediated IFN-beta production by fibroblasts and DCs. In addition, poly(dI:dC), a non-IFN inducer, also blocked poly(I:C)-induced IFN-beta induction. Since TLR3 is localized in the intracellular compartment of DCs where signaling occurs, modified dsRNAs may compete with poly(I:C) for binding to the cell-surface receptor that transfers dsRNA into TLR3-enriched vesicles. Thus, TLR3 recognizes a unique dsRNA structure that largely differs from those recognized by other dsRNA-binding proteins.
Volume 24(10)
Pages 614-23
Published 2005-10
DOI 10.1089/dna.2005.24.614
PMID 16225392
MeSH Cells, Cultured Cytokines / metabolism Fibroblasts / cytology Fibroblasts / metabolism Flow Cytometry Humans Interferon-beta / genetics Interferon-beta / metabolism* Interferon-beta / pharmacology Kidney / metabolism Lung / metabolism Membrane Glycoproteins / metabolism* Poly I-C / pharmacology* RNA, Double-Stranded / chemistry* RNA, Double-Stranded / metabolism Receptors, Cell Surface / metabolism* Ribose / chemistry* Toll-Like Receptor 3 Toll-Like Receptors
IF 2.918
Times Cited 49
Human and Animal Cells MRC-5