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首页> 外文期刊>Journal of endotoxin research >A designed TLR4/MD-2 complex to capture LPS.
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A designed TLR4/MD-2 complex to capture LPS.

机译：设计用于捕获LPS的TLR4 / MD-2复合体。

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The family of Toll-like receptors (TLRs) is involved in the defense of an organism to microbial attack. TLR4-induced signaling is involved in infectious diseases, chronic inflammatory diseases and sepsis; therefore, we aimed at modulating TLR4-signaling via ligand-binding soluble receptors. Because recognition of microbial structures shows some species-specific traits, we specifically selected the mouse model for later in vivo studies. We first prepared the N-terminally Flag-tagged mouse (m) recombinant (r) soluble (s) fusion proteins mrsTLR4-IgGFc (T4Fc) and mrsMD-2 in Drosophila melanogaster Schneider 2 (S2) cells. The function of these molecules was tested by inhibition of synthesis of pro-inflammatory cytokines after stimulation of mouse macrophage RAW 264.7 cells with purified lipopolysaccharide (LPS). T4Fc alone had no inhibitory activity; however, a T4Fc/MD-2 complex blocked LPS activity. By analogy with 'cytokine traps', we then prepared a designer molecule (LPS-Trap) by fusing MD-2 to the C-terminus of soluble TLR4 via a flexible linker. LPS-Trap significantly inhibited TNF production by LPS-stimulated RAW 264.7 cells. Thus, the T4Fc/MD-2 complex as well as the LPS-Trap blocked LPS activity in vitro and might thus represent a new therapeutic option in sepsis by neutralization of TLR4-activating ligands.
机译：Toll样受体（TLR）家族参与有机体对微生物攻击的防御。 TLR4诱导的信号传导涉及感染性疾病，慢性炎症性疾病和败血症。因此，我们旨在通过结合配体的可溶性受体来调节TLR4信号传导。由于对微生物结构的识别显示出某些物种特有的特征，因此我们专门选择了小鼠模型用于以后的体内研究。我们首先在果蝇Schneider 2（S2）细胞中制备了N端带有Flag标签的小鼠（m）重组（r）可溶性（s）融合蛋白mrsTLR4-IgGFc（T4Fc）和mrsMD-2。这些分子的功能通过用纯化的脂多糖（LPS）刺激小鼠巨噬细胞RAW 264.7细胞后抑制促炎性细胞因子合成来测试。单独的T4Fc没有抑制活性。然而，T4Fc / MD-2复合物阻断LPS活性。通过类似于“细胞因子陷阱”，我们然后通过柔性连接子将MD-2与可溶性TLR4的C末端融合，从而制备了设计分子（LPS-Trap）。 LPS诱捕剂显着抑制LPS刺激的RAW 264.7细胞产生的TNF。因此，T4Fc / MD-2复合物以及LPS-Trap在体外可阻断LPS活性，因此可通过中和TLR4激活配体来代表败血症的新治疗选择。

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