GRP78 Impairs LPS-Induced Inflammatory Production via Interacting with CD14
GRP78 Impairs LPS-Induced Inflammatory Production via Interacting with CD14
复制标题
GRP78 通过与 CD14 相互作用削弱 LPS 诱导的炎症产生
作者：
Kai Qin;Simin Ma;Heli Li;Min Wu;Yuanli Sun;Mingpeng Fu;Zilong Guo;Huifen Zhu;Feili Gong;Ping Lei;Guanxin Shen
78 kDa葡萄糖调节蛋白(GRP78)是一种应激诱导的伴侣蛋白，主要存在于内质网中。GRP78被描述为在细胞应激时释放，并具有抗炎或有利于消退炎症的细胞外特性。在目前的研究中，我们证实GRP78可抑制经GRP78处理的骨髓来源的树突状细胞(DC)产生内毒素诱导的致炎细胞因子。为了探讨其可能的作用机制，首先对GRP78进行了质膜结合实验。有趣的是，这种结合促进了Toll样受体(TLR4)的内吞作用，减少了TLR4在经GRP78处理的DC对内毒素的脱敏中起关键作用。鉴于分化簇(CD)14是TLR4内吞作用的重要调节因子，接下来我们将研究GRP78与CD14的相互作用。结果表明，GRP78与CD14共定位于细胞膜上，谷胱甘肽-S-转移酶-GRP78共沉淀CD14。在CD14基因敲除小鼠中，经GRP78处理的DC表面肿瘤坏死因子-α的下调和TLR4的减少被取消。总体而言，这些数据表明，GRP78通过靶向CD14介导TLR4的内吞作用，从而有利于炎症的消退。
The 78-kDa glucose-regulated protein (GRP78) is a stress-inducible chaperone that resides primarily in the endoplasmic reticulum. GRP78 has been described to be released at times of cellular stress and as having extracellular properties that are anti-inflammatory or favor the resolution of inflammation. In the current study, we confirmed that GRP78 impaired the production of lipopolysaccharide-induced pro-inflammatory cytokines in GRP78-treated bone-marrow-derived dendritic cells (DCs). To explore the underlying mechanism, first of all, GRP78 was checked to be bound to the plasma membrane. Interestingly, such binding promoted endocytosis of toll-like receptor (TLR) 4 and reduction in TLR4 on the plasma surface had a key role in desensitization of GRP78-treated DCs to lipopolysaccharide. Given that cluster of differentiation (CD)14 is a crucial regulator of TLR4 endocytosis, interaction of GRP78 with CD14 was investigated next. Data showed that GRP78 co-localized with CD14 on the plasma membrane and glutathione-S-transferase-GRP78 precipitated CD14. In CD14 knockout mice, down-regulation of tumor necrosis factor-α and reduction in TLR4 on the plasma surface were abrogated in GRP78-treated DCs. Overall, these data suggested that GRP78 mediates endocytosis of TLR4 by targeting CD14 to favor the resolution of inflammation.