REGULATION OF HUMAN MONONUCLEAR PHAGOCYTE MIGRATION BY CELL-SURFACE BINDING-PROTEINS FOR ADVANCED GLYCATION END-PRODUCTS
REGULATION OF HUMAN MONONUCLEAR PHAGOCYTE MIGRATION BY CELL-SURFACE BINDING-PROTEINS FOR ADVANCED GLYCATION END-PRODUCTS
复制标题
DOI：
10.1172/jci116442
复制
发表时间：
1993-05-01
影响因子：
15.9
通讯作者：
STERN, D
中科院分区：
文献类型：
--
作者：
SCHMIDT, AM;YAN, SD;STERN, D
蛋白质的非酶糖化在糖尿病中以加速的速率发生，并且可导致蛋白质的晚期糖化终产物（AGEs）的形成，其结合单核吞噬细胞（MP）并诱导趋化性。我们已经分离出两个细胞表面相关的结合蛋白，介导AGEs与牛内皮细胞的相互作用。这些蛋白质之一是免疫球蛋白受体超家族的新成员（称为AGEs或AGEs受体）;第二种是乳铁蛋白样多肽（LF-L）。使用这两个AGE结合蛋白的单特异性抗体，我们检测到免疫反应性物质的洗涤剂提取物从人类国会议员的蛋白质印迹。放射性配体结合研究表明，结合蛋白的抗体阻断I-125-AGE-白蛋白结合和MP的内吞作用。由可溶性AGE-白蛋白诱导的人MP的趋化性以剂量依赖性方式被针对AGE-结合蛋白的完整抗体、这些抗体的F（ab '）2片段和可溶性IgG阻止。当MP迁移响应N-甲酰-Met-Leu-Phe进行了研究，在一个趋化室与AGE-白蛋白吸附到室膜的上表面，MP的运动到下室减少，因为糖化蛋白与细胞表面上的LIF-L和LIF-L的相互作用。AGEs的吸引和保留MP的能力，通过植入聚四氟乙烯（PTFE）网浸渍AGE-白蛋白到大鼠：在4天内一个华丽的单核细胞浸润是明显的对比，缺乏显着的细胞反应PTFE与吸附的天然白蛋白。这些数据表明，在AGEs与人单核细胞的相互作用，AGEs可以作为一个病灶，以吸引MP在体内的核心作用，LF-L。
Nonenzymatic glycation of proteins occurs at an accelerated rate in diabetes and can lead to the formation of advanced glycation end products of proteins (AGEs), which bind to mononuclear phagocytes (MPs) and induce chemotaxis. We have isolated two cell surface-associated binding proteins that mediate the interaction of AGEs with bovine endothelial cells. One of these proteins is a new member of the immunoglobulin super-family of receptors (termed receptor for AGEs or RAGE); and the second is a lactoferrin-like polypeptide (LF-L). Using monospecific antibodies to these two AGE-binding proteins, we detected immunoreactive material on Western blots of detergent extracts from human MPs. Radioligand-binding studies demonstrated that antibody to the binding proteins blocked I-125-AGE-albumin binding and endocytosis by MPs. Chemotaxis of human MPs induced by soluble AGE-albumin was prevented in a dose-dependent manner by intact antibodies raised to the AGE-binding proteins, F(ab')2 fragments of these antibodies and by soluble RAGE. When MP migration in response to N-formyl-Met-Leu-Phe was studied in a chemotaxis chamber with AGE-albumin adsorbed to the upper surface of the chamber membrane, movement of MPs to the lower compartment was decreased because of interaction of the glycated proteins with RAGE and LF-L on the cell surface. The capacity of AGEs to attract and retain MPs was shown by implanting polytetrafluoroethylene (PTFE) mesh impregnated with AGE-albumin into rats: within 4 d a florid mononuclear cell infiltrate was evident in contrast to the lack of a significant cellular response to PTFE with adsorbed native albumin. These data indicate that RAGE and LF-L have a central role in the interaction of AGEs with human mononuclear cells and that AGEs can serve as a nidus to attract MPs in vivo.