Imani F, Horii Y, Suthanthiran M, Skolnik E Y, Makita Z, Sharma V, Sehajpal P, Vlassara H
Picower Institute for Medical Research, Manhasset, New York 11030.
J Exp Med. 1993 Dec 1;178(6):2165-72. doi: 10.1084/jem.178.6.2165.
During normal aging and in chronic diabetes the excessive accumulation of reactive glucose-protein or glucose-lipid adducts known as advanced glycosylation endproducts (AGEs) has been shown to induce tissue dysfunction, in part through interaction with AGE-specific receptors on monocyte/macrophages and other cells. Recognizing that circulating lymphocytes trafficking through tissues interact with tissue AGEs, we searched for the expression of AGE-binding sites on peripheral blood T lymphocytes. Resting rat and human T cells bound 125I-AGE-albumin with an affinity of 7.8 x 10(7) M-1, whereas, after stimulation with phytohemagglutinin (PHA) for 48 h, binding affinity increased to 5.8 x 10(8) M-1. Flow cytometric analysis of resting rat T cells using polyclonal antibodies raised against rat liver AGE-binding proteins (p60 and p90) revealed the constitutive expression of both immunoreactivities. The number of resting CD4+ and CD8+ T cells positive for anti-p60 antibody binding (34.2 and 58.5%, respectively) increased to 92 and 90% of cells after 48-h stimulation with PHA. Exposure of PHA-activated T lymphocytes to AGE-albumin enhanced expression of interferon gamma (IFN-gamma) mRNA 10-fold and induced greater elaboration of the mature protein than did exposure to unmodified protein or PHA treatment alone. These data indicate that T cells contain an inducible system of surface receptors for AGE-modified proteins, and that receptor occupancy is linked to lymphokine production. This T cell AGE-receptor system might serve to target lymphocytes to AGE-rich tissues and involve them in the regulation of tissue homeostasis either by assisting in macrophage-dependent clearance of AGE-proteins, or by exerting direct antiproliferative action on mesenchymal cells. Under conditions of excessive AGE-protein and AGE lipid accumulation (e.g., aging and diabetes), enhanced production of AGE-induced IFN-gamma may accelerate immune responses that contribute to tissue injury.
在正常衰老过程以及慢性糖尿病中，已知的晚期糖基化终产物（AGEs），即反应性葡萄糖 - 蛋白质或葡萄糖 - 脂质加合物的过度积累，已被证明会诱导组织功能障碍，部分原因是通过与单核细胞/巨噬细胞及其他细胞上的AGE特异性受体相互作用。鉴于循环淋巴细胞在组织中游走时会与组织AGEs相互作用，我们研究了外周血T淋巴细胞上AGE结合位点的表达情况。静息状态的大鼠和人类T细胞以7.8×10⁷ M⁻¹的亲和力结合¹²⁵I - AGE - 白蛋白，而在用植物血凝素（PHA）刺激48小时后，结合亲和力增加到5.8×10⁸ M⁻¹。使用针对大鼠肝脏AGE结合蛋白（p60和p90）产生的多克隆抗体对静息大鼠T细胞进行流式细胞术分析，揭示了两种免疫反应性的组成性表达。抗p60抗体结合阳性的静息CD4⁺和CD8⁺ T细胞数量（分别为34.2%和58.5%）在用PHA刺激48小时后增加到细胞总数的92%和90%。将PHA激活的T淋巴细胞暴露于AGE - 白蛋白中，与暴露于未修饰的蛋白质或单独的PHA处理相比，干扰素γ（IFN - γ）mRNA的表达增强了10倍，并诱导成熟蛋白的释放量更大。这些数据表明，T细胞含有一个可诱导的针对AGE修饰蛋白的表面受体系统，并且受体占据与淋巴因子产生相关联。这种T细胞AGE受体系统可能有助于将淋巴细胞靶向富含AGE的组织，并通过协助巨噬细胞依赖的AGE蛋白清除，或对间充质细胞发挥直接的抗增殖作用，从而参与组织稳态的调节。在AGE - 蛋白质和AGE脂质过度积累的情况下（例如衰老和糖尿病），AGE诱导的IFN - γ产生增加可能会加速导致组织损伤的免疫反应。
