Toll‐like receptor (TLR)‐4 mediates anti‐β2GPI/β2GPI‐induced tissue factor expression in THP‐1 cells
Toll‐like receptor (TLR)‐4 mediates anti‐β2GPI/β2GPI‐induced tissue factor expression in THP‐1 cells
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DOI：
10.1111/j.1365-2249.2010.04291.x
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发表时间：
2011-02
影响因子：
4.6
通讯作者：
Hong Zhou;Y. Yan;Guo-ying Xu;B. Zhou;Hai-ping Wen;Donglin Guo;Fang Zhou;Haibo Wang
中科院分区：
文献类型：
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作者：
Hong Zhou;Y. Yan;Guo-ying Xu;B. Zhou;Hai-ping Wen;Donglin Guo;Fang Zhou;Haibo Wang
我们前期的研究表明，细胞表面的膜联蛋白A2（ANX 2）可作为一种介质，通过抗β2-糖蛋白I/β2-糖蛋白I复合物（anti-β2GPI/β2GPI）刺激单核细胞表达组织因子（TF）。然而，ANX 2不是跨膜蛋白，并且缺乏细胞内信号转导途径。越来越多的证据表明，Toll样受体4（TLR-4）可能在抗β2GPI/β2GPI诱导的TF表达细胞中充当细胞内信号转导的“接头”。在当前的研究中，我们研究了TLR-4及其相关分子髓样分化蛋白2（MD-2）和髓样分化因子88（MyD 88）在抗β2GPI/β2GPI诱导的表达TF的人单核细胞衍生的THP-1（人急性单核细胞白血病）细胞中的作用。还探讨了TLR-4和ANX 2在此过程中的关系。抗β 2 GPI（10 μg/ml）/β 2 GPI（100 μ g/ml）复合物作用于THP-1细胞后，THP-1细胞TLR-4、MD-2和MyD 88的表达与TF一起沿着增加。加入与MD-2配体竞争的紫杉醇可抑制抗β2GPI/β2GPI对TLR-4、MD-2、MyD 88和TF表达的影响。THP-1细胞裂解物中的ANX-2和TLR-4均可与已偶联至柱（β 2GPI-Affi-Gel）的β2GPI结合。此外，尽管用类似浓度的抗β2GPI/β2GPI复合物处理，但在用ANX 2特异性RNA干扰（RNAi）慢病毒（LV-RNAi-ANX 2）感染的THP-1细胞中TLR-4、MD-2、MyD 88和TF表达显著降低。这些结果表明TLR-4及其信号转导通路参与了抗β2GPI/β2GPI诱导的THP-1细胞TF表达，并且TLR-4与ANX 2的作用是紧密协同的。
Our previous study demonstrated that annexin A2 (ANX2) on cell surface could function as a mediator and stimulate tissue factor (TF) expression of monocytes by anti‐β2‐glycoprotein I/β2‐glycoprotein I complex (anti‐β2GPI/β2GPI). However, ANX2 is not a transmembrane protein and lacks the intracellular signal transduction pathway. Growing evidence suggests that Toll‐like receptor 4 (TLR‐4) might act as an ‘adaptor’ for intracellular signal transduction in anti‐β2GPI/β2GPI‐induced TF expressing cells. In the current study, we investigated the roles of TLR‐4 and its related molecules, myeloid differentiation protein 2 (MD‐2) and myeloid differentiation factor 88 (MyD88), in anti‐β2GPI/β2GPI‐induced TF expressing human monocytic‐derived THP‐1 (human acute monocytic leukaemia) cells. The relationship of TLR‐4 and ANX2 in this process was also explored. Along with TF, expression of TLR‐4, MD‐2 and MyD88 in THP‐1 cells increased significantly when treated by anti‐β2GPI (10 µg/ml)/β2GPI (100 µg/ml) complex. The addition of paclitaxel, which competes with the MD‐2 ligand, could inhibit the effects of anti‐β2GPI/β2GPI on TLR‐4, MD‐2, MyD88 and TF expression. Both ANX2 and TLR‐4 in THP‐1 cell lysates could bind to β2GPI that had been conjugated to a column (β2GPI‐Affi‐Gel). Furthermore, TLR‐4, MD‐2, MyD88 and TF expression was remarkably diminished in THP‐1 cells infected with ANX2‐specific RNA interference (RNAi) lentivirus (LV‐RNAi‐ANX2), in spite of treatment with a similar concentration of anti‐β2GPI/β2GPI complex. These results indicate that TLR‐4 and its signal transduction pathway contribute to anti‐β2GPI/β2GPI‐induced TF expression in THP‐1 cells, and the effects of TLR‐4 with ANX2 are tightly co‐operative.