國家衛生研究院 NHRI:Item 3990099045/4067
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    題名: Anti-inflammatory actions of Syk inhibitors in macrophages involve non-specific inhibition of toll-like receptors-mediated JNK signaling pathway
    作者: Lin, YC;Huang, DY;Chu, CL;Lin, WW
    貢獻者: Immunology Research Center
    摘要: Toll-like receptors (TLRs) are a major family of pattern recognition receptors (PRRs) and play a crucial role in innate immune system. Even though non-receptor spleen tyrosine kinase (Syk) is a key signaling molecule of immunoreceptor tyrosine-based activation motifs-containing immunoreceptors, its role in TLRs signaling is not clearly understood. Herein, we investigated the role of Syk in TLR-mediated signaling and gene regulation. In bone marrow-derived macrophages (BMDMs) and RAW 264.7 macrophages, treatment of poly(I:C), LPS and CpG, which are specific ligands of TLR3, TLR4 and TLR9, respectively, can increase the mRNA levels of several pro-inflammatory cytokines and mediators, including IFNβ, TNFα, MIP2, IL-6, IL-12β, iNOS and COX-2. The gene upregulation caused by TLR was inhibited by Syk inhibitor (SykI) and JNK inhibitor (SP600125). Accordingly we found the abilities of TLR3, TLR4 and TLR9 ligands to induce Syk and JNK activation, as evidenced by increased Syk autophosphorylation on Y519/Y520, JNK phosphorylation and both kinase activities. We also found that TLRs-mediated JNK activation, but not IKK, p38 and ERK activation as well as IκB degradation in BMDM and RAW 264.7 cells, was blocked by SykI. Nevertheless TLR-mediated JNK activation as well as the increased protein expression of iNOS and COX-2 remained unchanged when Syk protein was knockdown by siRNA approach. With in vitro kinase assay we found two commercial Syk inhibitors (SykI, and BAY61-3606) have direct inhibition on JNK activity. These findings demonstrate that the non-selective action of SykI on JNK should be taken into consideration upon using them to explore the biological actions of Syk.
    日期: 2010-04
    關聯: Molecular Immunology. 2010 Apr;47(7-8):1569-1578.
    Link to: http://dx.doi.org/10.1016/j.molimm.2010.01.008
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0161-5890&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000277862300023
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=77950630062
    顯示於類別:[朱清良(2005-2010)] 期刊論文

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