GRP78 Impairs Production of Lipopolysaccharide-Induced Cytokines by Interaction with CD14.
GRP78 Impairs Production of Lipopolysaccharide-Induced Cytokines by Interaction with CD14.
复制标题
DOI：
10.3389/fimmu.2017.00579
复制
发表时间：
2017
影响因子：
7.3
通讯作者：
Shen G
中科院分区：
文献类型：
--
作者：
Qin K;Ma S;Li H;Wu M;Sun Y;Fu M;Guo Z;Zhu H;Gong F;Lei P;Shen G
78 kDa 葡萄糖调节蛋白 (GRP78) 是一种应激诱导型伴侣，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炎症消退的细胞外特性。在当前的研究中，我们证实GRP78损害了GRP78处理的骨髓源性树突状细胞（DC）中脂多糖诱导的促炎细胞因子的产生。为了探究其潜在机制，首先检查GRP78是否与质膜结合。有趣的是，这种结合促进了Toll样受体（TLR）4的内吞作用，并且血浆表面TLR4的减少在GRP78处理的DC对脂多糖的脱敏中发挥了关键作用。鉴于分化簇 (CD)14 是 TLR4 内吞作用的关键调节因子，接下来研究了 GRP78 与 CD14 的相互作用。数据显示，GRP78 与 CD14 共定位于质膜上，并且谷胱甘肽-S-转移酶-GRP78 沉淀 CD14。在 CD14 敲除小鼠中，GRP78 处理的 DC 中肿瘤坏死因子-α 的下调和血浆表面 TLR4 的减少被消除。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.