High glucose and interleukin-1β downregulate interleukin-1 type I receptor (IL-1RI) in retinal endothelial cells by enhancing its degradation by a lysosome-dependent mechanism
High glucose and interleukin-1β downregulate interleukin-1 type I receptor (IL-1RI) in retinal endothelial cells by enhancing its degradation by a lysosome-dependent mechanism
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DOI：
10.1016/j.cyto.2009.11.014
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发表时间：
2010-03-01
期刊：
影响因子：
3.8
通讯作者：
Ambrosio, Antonio Francisco
中科院分区：
文献类型：
--
作者：
Aveleira, Celia;Castilho, Aurea;Ambrosio, Antonio Francisco
糖尿病视网膜病变被认为是一种低度慢性炎症性疾病。视网膜中IL-1β的产生增加，这一发现与血-视网膜屏障通透性的增加有关，提示IL-1β可能在糖尿病视网膜病变的发病机制中起重要作用。然而，在这种背景下，没有人关注白介素1I型受体(IL-1RI)，它是负责IL-1β触发效应的受体。因此，我们研究了高糖和IL-1β对视网膜内皮细胞IL-1RI调节的影响。在高糖、甘露醇或IL-1β作用下(1-24小时)，视网膜内皮细胞IL-1RI蛋白水平呈时间依赖性下调。长期(7天)接触高糖或甘露醇也会降低IL-1RI蛋白含量。IL-1RI的下调是由于其被IL-1β激活，因为它被抗IL-1RI或抗1L-1β抗体所抑制。此外，溶酶体抑制剂氯喹和氯化铵可以阻止IL-1RI的下调，但蛋白酶体抑制剂MG132和lactacystin不能阻止IL-1RI的下调。我们还发现，在高糖或IL-1β处理后，IL-1RI移位到细胞核。综上所述，我们的结果表明，可能是由于渗透压所致的高血糖和IL-1β下调了视网膜内皮细胞的IL-1RI。IL-1RI的下调是由其激活触发的，至少部分是由于溶酶体的降解。高糖和IL-1β也增加了IL-1RI向细胞核的移位。(C)2009爱思唯尔有限公司。保留所有权利。
Diabetic retinopathy has been considered a low-grade chronic inflammatory disease. The production of interleukin-1 beta (IL-1 beta) in the retina is increased, and this finding has been correlated with an increase in blood-retinal barrier permeability, suggesting that IL-1 beta might have an important role in the pathogenesis of diabetic retinopathy. However, in this context, no attention has been given to interleukin-1 type I receptor (IL-1RI), which is the receptor responsible for IL-1 beta triggered effects. Therefore, we investigated the effect of high glucose and IL-1 beta on the IL-1RI regulation in retinal endothelial cells. A time-dependent downregulation of IL-1RI protein levels was detected in retinal endothelial cells exposed (1-24 h) to high glucose, mannitol or IL-1 beta. Long-term exposure (7 days) to high glucose or mannitol also decreased IL-1RI protein content. IL-1RI downregulation was due to its activation by IL-1 beta, since it was inhibited by the presence of anti-IL-1RI or anti-1L-1 beta antibodies. Moreover, IL-1RI downregulation was prevented by lysosome inhibitors, chloroquine and ammonium chloride, but not by proteasome inhibitors, MG132 and lactacystin. We also found that IL-1RI translocates to the nucleus after high glucose or IL-1 beta treatment. In conclusion, our results indicate that high glucose, probably due to osmotic stress, and IL-1 beta downregulate IL-1RI in retinal endothelial cells. The downregulation of IL-1RI is triggered by its activation and is due, at least partially, to lysosomal degradation. High glucose and IL-1 beta also enhance the translocation of IL-1RI to the nucleus. (C) 2009 Elsevier Ltd. All rights reserved.