Spleen tyrosine kinase regulates AP-1 dependent transcriptional response to minimally oxidized LDL.
Spleen tyrosine kinase regulates AP-1 dependent transcriptional response to minimally oxidized LDL.
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DOI：
10.1371/journal.pone.0032378
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Miller YI
中科院分区：
文献类型：
--
作者：
Choi SH;Wiesner P;Almazan F;Kim J;Miller YI
低密度脂蛋白（LDL）的氧化修饰将其转化为模式识别受体识别的内源性配体。我们已经证明，最低限度氧化的低密度脂蛋白（mmLDL）结合CD 14和介导TLR 4/MD-2依赖性反应的巨噬细胞，其中许多是MyD 88的独立。我们还证明，mmLDL激活导致脾酪氨酸激酶（Syk）募集至TLR 4，TLR 4和Syk磷酸化。在这项研究中，我们产生了巨噬细胞特异性Syk敲除小鼠，并在我们的研究中使用原代Syk−/−巨噬细胞。我们证明，Syk介导的ERK 1/2和JNK的磷酸化，这反过来磷酸化c-Fos和c-Jun，分别通过体外激酶测定评估。c-Jun磷酸化也由IKKε介导。c-Jun和c-Fos与共有DNA位点结合，从而完成AP-1转录复合物并诱导CXCL 2和IL-6的表达。这些结果表明，Syk在TLR 4介导的巨噬细胞对宿主产生的配体（如mmLDL）的应答中起关键作用，随后激活AP-1转录程序。
Oxidative modification of low-density lipoprotein (LDL) turns it into an endogenous ligand recognized by pattern-recognition receptors. We have demonstrated that minimally oxidized LDL (mmLDL) binds to CD14 and mediates TLR4/MD-2-dependent responses in macrophages, many of which are MyD88-independent. We have also demonstrated that the mmLDL activation leads to recruitment of spleen tyrosine kinase (Syk) to TLR4 and TLR4 and Syk phosphorylation. In this study, we produced a macrophage-specific Syk knockout mouse and used primary Syk−/− macrophages in our studies. We demonstrated that Syk mediated phosphorylation of ERK1/2 and JNK, which in turn phosphorylated c-Fos and c-Jun, respectively, as assessed by an in vitro kinase assay. c-Jun phosphorylation was also mediated by IKKε. c-Jun and c-Fos bound to consensus DNA sites and thereby completed an AP-1 transcriptional complex and induced expression of CXCL2 and IL-6. These results suggest that Syk plays a key role in TLR4-mediated macrophage responses to host-generated ligands, like mmLDL, with subsequent activation of an AP-1 transcription program.
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影响因子：
32.4
作者：
Kawai, T;Adachi, O;Akira, S
通讯作者：
Akira, S
DOI：
10.1084/jem.194.1.79
发表时间：
2001-07-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Schromm AB;Lien E;Henneke P;Chow JC;Yoshimura A;Heine H;Latz E;Monks BG;Schwartz DA;Miyake K;Golenbock DT
通讯作者：
Golenbock DT
影响因子：
3.6
作者：
Lin, Ying-Cing;Huang, Duen-Yi;Lin, Wan-Wan
通讯作者：
Lin, Wan-Wan
影响因子：
20.1
作者：
Miller YI;Choi SH;Wiesner P;Fang L;Harkewicz R;Hartvigsen K;Boullier A;Gonen A;Diehl CJ;Que X;Montano E;Shaw PX;Tsimikas S;Binder CJ;Witztum JL
通讯作者：
Witztum JL
影响因子：
20.1
作者：
Choi SH;Harkewicz R;Lee JH;Boullier A;Almazan F;Li AC;Witztum JL;Bae YS;Miller YI
通讯作者：
Miller YI