Mrp8 and Mrp14 are endogenous activators of Toll- like receptor 4, promoting lethal, endotoxin-induced shock
Mrp8 and Mrp14 are endogenous activators of Toll- like receptor 4, promoting lethal, endotoxin-induced shock
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DOI：
10.1038/nm1638
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发表时间：
2007-09-01
期刊：
影响因子：
82.9
通讯作者：
Roth, Johannes
中科院分区：
文献类型：
--
作者：
Vogl, Thomas;Tenbrock, Klaus;Roth, Johannes
为了确定脓毒症期间调节炎症级联的新成分，我们表征了吞噬细胞中两种丰富的细胞质蛋白骨髓相关蛋白 8（Mrp8，S100A8）和骨髓相关蛋白 14（Mrp14，S100A9）的功能。我们现在证明，缺乏Mrp8-Mrp14复合物的小鼠可以免受内毒素诱导的致死性休克和大肠杆菌诱导的腹部败血症的影响。这两种蛋白在吞噬细胞激活过程中都会释放，Mrp8-Mrp14 复合物会放大内毒素引发的吞噬细胞炎症反应。 Mrp8 是一种活性成分，可诱导骨髓分化初级反应蛋白 88 的细胞内易位以及白细胞介素 1 受体相关激酶 1 和核因子 κ B 的激活，从而导致肿瘤坏死因子 α (TNF-α) 表达升高。使用表达非功能性 Toll 样受体 4 (TLR4) 的吞噬细胞、转染 TLR4、CD14 和 MD2 的 HEK293 细胞，并通过体外表面等离子共振研究，我们证明 Mrp8 与 TLR4-MD2 复合物特异性相互作用，从而代表 TLR4 的内源配体。因此，Mrp8-Mrp14 复合物是新的炎症成分，可在 TNF α 依赖性效应上游的脓毒症期间放大吞噬细胞的激活。
To identify new components that regulate the inflammatory cascade during sepsis, we characterized the functions of myeloidrelated protein-8 (Mrp8, S100A8) and myeloid-related protein-14 (Mrp14, S100A9), two abundant cytoplasmic proteins of phagocytes. We now demonstrate that mice lacking Mrp8-Mrp14 complexes are protected from endotoxin-induced lethal shock and Escherichia coli-induced abdominal sepsis. Both proteins are released during activation of phagocytes, and Mrp8-Mrp14 complexes amplify the endotoxin-triggered inflammatory responses of phagocytes. Mrp8 is the active component that induces intracellular translocation of myeloid differentiation primary response protein 88 and activation of interleukin-1 receptor-associated kinase-1 and nuclear factor-kappa B, resulting in elevated expression of tumor necrosis factor-alpha (TNF-alpha). Using phagocytes expressing a nonfunctional Toll- like receptor 4 (TLR4), HEK293 cells transfected with TLR4, CD14 and MD2, and by surface plasmon resonance studies in vitro, we demonstrate that Mrp8 specifically interacts with the TLR4-MD2 complex, thus representing an endogenous ligand of TLR4. Therefore Mrp8-Mrp14 complexes are new inflammatory components that amplify phagocyte activation during sepsis upstream of TNF alpha-dependent effects.