國家衛生研究院 NHRI:Item 3990099045/7833
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    题名: The inducible Nitric-oxide Synthase (iNOS)/Src axis mediates toll-like receptor 3 tyrosine 759 phosphorylation and enhances its signal transduction, leading to interferon-beta synthesis in macrophages
    其它题名: The inducible Nitric-oxide Synthase (iNOS)/Src axis mediates toll-like receptor 3 tyrosine 759 phosphorylation and enhances its signal transduction, leading to interferon-β synthesis in macrophages
    作者: Hsieh, MY;Chang, MY;Chen, YJ;Li, YK;Chuang, TH;Yu, GY;Cheung, CH;Chen, HC;Maa, MC;Leu, TH
    贡献者: Immunology Research Center;Division of Infectious Diseases
    摘要: Double-stranded RNA (dsRNA) induces phosphorylation of Toll-like receptor 3 (TLR3) at Tyrosine 759 (Y759) and subsequently triggers signaling pathways to promote interferon-beta (IFN-beta) production. In this study, we found that dsRNA-stimulation induces biphasic TLR3 Y759-phosphorylation in macrophages. In addition to the immediate TLR3 Y759-phosphorylation, we identified a second wave of Y759-phosphorylation accompanied with the increase of both Src and ifn-beta transcription in the later phase of dsRNA-stimulation. Interestingly, Src phosphorylated TLR3 Y759 in vitro and in vivo. However, knockdown of Src abolished the late phase of TLR3 Y759-phosphorlyation and decreased the nuclear accumulation of interferon regulatory factors (IRFs) 3 and 7 and IFN-beta production. Re-introduction of Src restored all these molecular changes. Notably, via down-regulation of Src, dsRNA-elicited TLR3 Y759-phosphorylation, the nuclear accumulation of IRF3/IRF7, and IFN-beta generation were inhibited in inducible nitric oxide synthase (iNOS)-null macrophages. TLR3 knockdown destabilized Src and reduced the nuclear level of IRF3/IRF7 and IFN-beta production in macrophages exposed to LPS (a TLR4 ligand known to induce Src and IFN-beta expression). Ectopic expression of wild type TLR3, but not its 759-phenylalanine mutant, restored Src activity and ifn-beta transcription. Taken together, these results suggested an essential role of iNOS/Src/TLR3 axis in IFN-beta production in macrophages.
    日期: 2014-03
    關聯: Journal of Biological Chemistry. 2014 Mar;289(13):9208-9220.
    Link to: http://dx.doi.org/10.1074/jbc.M113.508663
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1083-351X&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000333472100039
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84897415714
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