Miyata T, Hori O, Zhang J, Yan S D, Ferran L, Iida Y, Schmidt A M
Department of Internal Medicine, Branch Hospital, Nagoya University School of Medicine, Japan.
J Clin Invest. 1996 Sep 1;98(5):1088-94. doi: 10.1172/JCI118889.
An important component of amyloid fibrils in dialysis-related amyloidosis is a form of beta2microglobulin modified with advanced glycation end products (AGEs) of the Maillard reaction, known as AGE-beta2M. We demonstrate here that the interaction of AGE-beta2M 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. 125I-AGE-beta2M bound to immobilized RAGE or to MPs in a specific, dose-dependent manner (Kd approximately 53.5 and approximately 81.6 nM, respectively), a process inhibited in the presence of RAGE blockade. AGE-beta2M-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-beta2M 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-beta2M 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-beta2M-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.
透析相关淀粉样变中淀粉样纤维的一个重要成分是一种经美拉德反应的晚期糖基化终产物（AGEs）修饰的β2微球蛋白，称为AGE-β2M。我们在此证明，AGE-β2M与单核吞噬细胞（MPs）的相互作用是由AGE受体（RAGE）介导的，单核吞噬细胞在透析相关淀粉样变的炎症性关节病发病机制中起重要作用。125I-AGE-β2M以特异性、剂量依赖性方式与固定化的RAGE或MPs结合（解离常数分别约为53.5 nM和约81.6 nM），在存在RAGE阻断的情况下该过程受到抑制。过量的可溶性RAGE（sRAGE）或抗RAGE IgG可阻止AGE-β2M介导的单核细胞趋化作用。暴露于AGE-β2M的MPs诱导肿瘤坏死因子-α（TNF）表达是由RAGE的结合引起的，因为添加sRAGE可阻止TNF转录本的出现和TNF抗原释放到培养上清液中，该过程至少部分由氧化应激介导。AGE-β2M可降低细胞色素c，N-乙酰半胱氨酸可抑制MPs对TNF的分泌。与这些数据一致，对一名长期血液透析患者的富含AGE的淀粉样沉积物进行免疫组织化学研究发现，浸润这些病变的MPs中RAGE呈阳性染色。这些数据表明，RAGE是体内形成的AGEs的中心结合位点，并提示AGE-β2M-MP-RAGE相互作用可能有助于长期血液透析患者淀粉样沉积物中炎症反应的启动，这一过程最终可能导致骨骼和关节破坏。
