The extra domain A of fibronectin activates toll-like receptor 4
The extra domain A of fibronectin activates toll-like receptor 4
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DOI：
10.1074/jbc.m100099200
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发表时间：
2001-03-30
影响因子：
4.8
通讯作者：
Strauss, JF
中科院分区：
文献类型：
--
作者：
Okamura, Y;Watari, M;Strauss, JF
细胞纤维连接蛋白含有一个编码III型重复额外结构域A （EDA）的选择性剪接外显子，是在组织损伤时产生的，纤维连接蛋白片段与生理和病理过程有关，特别是与炎症相关的组织重塑。由于含有EDA的纤维连接蛋白片段产生的细胞反应类似于细菌脂多糖（LPS）引起的细胞反应，我们检测了重组EDA激活toll样受体4 （TLR4）的能力，TLR4是LPS刺激的信号受体。我们发现，重组EDA，而不是其他重组纤维连接蛋白结构域，激活在通常缺乏这种toll样受体的细胞类型（HEK 293细胞）中表达的人TLR4。EDA对TLR4的刺激依赖于TLR4辅助蛋白MD-2的共表达。与LPS不同的是，EDA的活性是热敏的，并且在LPS结合抗生素多粘菌素B和强效LPS拮抗剂E5564的存在下持续存在，这完全抑制了LPS对TLR4的激活。这些观察结果提供了一种机制，通过这种机制，含有EDA的纤维连接蛋白片段促进了参与炎症反应的基因的表达。
Cellular fibronectin, which contains an alternatively spliced exon encoding type III repeat extra domain A (EDA), is produced in response to tissue injury, Fragments of fibronectin have been implicated in physiological and pathological processes, especially tissue remodeling associated with inflammation. Because EDA-containing fibronectin fragments produce cellular responses similar to those provoked by bacterial lipopolysaccharide (LPS), we examined the ability of recombinant EDA to activate Toll-like receptor 4 (TLR4), the signaling receptor stimulated by LPS. We found that recombinant EDA, but not other recombinant fibronectin domains, activates human TLR4 expressed in a cell type (HEK 293 cells) that normally lacks this Toll-like receptor. EDA stimulation of TLR4 was dependent upon co-expression of MD-2, a TLR4 accessory protein. Unlike LPS, the activity of EDA was heat-sensitive and persisted in the presence of the LPS-binding antibiotic polymyxin B and a potent LPS antagonist, E5564, which completely suppressed LPS activation of TLR4, These observations provided a mechanism by which EDA-containing fibronectin fragments promote expression of genes involved in the inflammatory response.