The receptor for advanced glycation end products (RAGE) is a central mediator of the interaction of AGE-beta(2)microglobulin with human mononuclear phagocytes via an oxidant-sensitive pathway - Implications for the pathogenesis of dialysis-related amyloidosis
The receptor for advanced glycation end products (RAGE) is a central mediator of the interaction of AGE-beta(2)microglobulin with human mononuclear phagocytes via an oxidant-sensitive pathway - Implications for the pathogenesis of dialysis-related amyloidosis
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DOI：
10.1172/jci118889
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发表时间：
1996-09-01
影响因子：
15.9
通讯作者：
Schmidt, AM
中科院分区：
文献类型：
--
作者：
Miyata, T;Hori, O;Schmidt, AM
在透析相关性淀粉样变性中，淀粉样原纤维的一个重要组成部分是一种β(2)微球蛋白，被美拉德反应的晚期糖基化终产物（AGEs）修饰，称为age - β (2)M。我们在这里证明了age - β (2)M与单核吞噬细胞（MPs）的相互作用是由age受体（RAGE）介导的，而MPs是在透析相关淀粉样变性的炎性关节病发病机制中起重要作用的细胞。I-125-AGE-beta(2)M以特定的剂量依赖性方式结合到固定的RAGE或MPs上（K-d分别约为53.5和81.6 nM），这一过程在RAGE阻断下被抑制，过量的sRAGE或抗RAGE IgG阻止了AGE-beta(2)M介导的单核细胞趋化性，RAGE导致暴露于AGE-beta(2)M的MPs诱导肿瘤坏死因子α (TNF)表达。由于添加sRAGE（至少部分由氧化应激介导）阻止了TNF转录物的出现和TNF抗原释放到培养上清液中，AGE β (2)M降低了细胞色素c，而n -乙酰半胱氨酸抑制了MPs对TNF的合成。与这些数据一致，长期血液透析患者的age -淀粉样蛋白沉积的免疫组织化学研究显示，浸润这些病变的MPs中RAGE阳性。这些数据表明RAGE是体内形成的AGEs的中心结合位点，并表明age - β (2)M-MP-RAGE相互作用可能有助于长期血液透析患者淀粉样蛋白沉积物的炎症反应的启动，这一过程可能最终导致骨骼和关节破坏。
An important component of amyloid fibrils in dialysis-related amyloidosis is a form of beta(2)microglobulin modified with advanced glycation end products (AGEs) of the Maillard reaction, known as AGE-beta(2)M. We demonstrate here that the interaction of AGE-beta(2)M with mononuclear phagocytes (MPs), cells important in the pathogenesis of the inflammatory arthropathy of dialysis-related amyloidosis, is mediated by the receptor for AGEs, or RAGE. I-125-AGE-beta(2)M bound to immobilized RAGE or to MPs in a specific, dose-dependent manner (K-d approximate to 53.5 and approximate to 81.6 nM, respectively), a process inhibited in the presence of RAGE blockade, AGE-beta(2)M-mediated monocyte chemotaxis was prevented by excess sRAGE or anti-RAGE IgG, Induction of tumor necrosis factor-alpha (TNF) expression by MPs exposed to AGE-beta(2)M resulted from engagement of RAGE, as appearances of TNF transcripts and TNF antigen release into culture supernatants were prevented by addition of sRAGE, a process mediated, at least in part, by oxidant stress, AGE beta(2)M reduced cytochrome c and the elaboration of TNF by MPs was inhibited by N-acetylcysteine. Consistent with these data, immunohistochemical studies of AGE-laden amyloid deposits of a long-term hemodialysis patient revealed positive staining for RAGE in the MPs infiltrating these lesions. These data indicate that RAGE is a central binding site for AGEs formed in vivo and suggest that AGE-beta(2)M-MP-RAGE interaction likely contributes to the initiation of an inflammatory response in amyloid deposits of long-term hemodialysis patients, a process which may ultimately lead to bone and joint destruction.