Interferon-beta induction through toll-like receptor 3 depends on double-stranded RNA structure.
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.
Okahira
Satoyo
S
Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari-ku, Osaka, Japan.
Nishikawa
Fumiko
F
Nishikawa
Satoshi
S
Akazawa
Takashi
T
Seya
Tsukasa
T
Matsumoto
Misako
M
D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology*; D012330:RNA, Double-Stranded / Q000737:chemistry* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012266:Ribose / Q000737:chemistry*; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors
D016207:Cytokines; D008562:Membrane Glycoproteins; D012330:RNA, Double-Stranded; D011956:Receptors, Cell Surface; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D012266:Ribose; D016899:Interferon-beta; D011070:Poly I-C