Suppr超能文献

JNK 和 ATF4 作为肿瘤坏死因子-α刺激的晚期糖基化终产物受体脱落的两个重要平台。

JNK and ATF4 as two important platforms for tumor necrosis factor-α-stimulated shedding of receptor for advanced glycation end products.

机构信息

Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.

Department of Endocrinology, Metabolism, and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan; and.

出版信息

FASEB J. 2019 Mar;33(3):3575-3589. doi: 10.1096/fj.201701553RR. Epub 2018 Nov 19.

Abstract

Soluble receptor for advanced glycation end products (sRAGE), shed from cell surfaces, is found in human circulation and has been implicated in cardiovascular disease. Its pathophysiological regulation and underlying mechanisms are scarcely understood. In endothelium-specific human RAGE transgenic mice, human sRAGE was detected in circulation, whereas its level was markedly increased after LPS treatment. That increase was preceded by a rapid rise in TNF-α level. Treatment with TNF-α also significantly increased serum sRAGE. In human microvascular endothelial cells or human umbilical vein endothelial cells with RAGE overexpression, TNF-α markedly induced RAGE shedding, which was dependent on MMP9 and ADAM10. TNF-α-stimulated MMP9 expression was completely dependent on JNK activation, with its inhibition partially effective in suppressing TNF-α-induced RAGE shedding. In contrast, TNF-α transiently induced activation transcription factor (ATF)4, a major component in unfolded protein response (UPR), whereas knockdown of ATF4 abrogated TNF-α-stimulated RAGE shedding. Protein levels of the pro and activated forms of ADAM10 were also decreased by ATF4 knockdown, whereas inhibition of other components of UPR, including XBP1 and ATF6, failed to block TNF-α-stimulated RAGE shedding. Although the endoplasmic reticulum stressors thapsigargin and tunicamycin induced markedly and sustained expression of ATF4 and XBP-1, they did not induce RAGE shedding to the same level as TNF-α, suggesting that ATF4 is necessary but not sufficient alone for TNF-α-mediated RAGE shedding. ATF4 inhibition did not affect TNF-α-stimulated MMP9 expression, whereas inhibition of JNK activity did not influence ADAM10 activation. Thus, inflammatory cascades including TNF-α induced RAGE shedding in endothelial cells in vivo and in vitro. JNK and ATF4 may be 2 platforms for regulation of TNF-α-stimulated RAGE shedding.-Miyoshi, A., Koyama, S., Sasagawa-Monden, M., Kadoya, M., Konishi, K., Shoji, T., Inaba, M., Yamamoto, Y., Koyama, H. JNK and ATF4 as two important platforms for tumor necrosis factor-α-stimulated shedding of receptor for advanced glycation end products.

摘要

可溶性晚期糖基化终产物受体(sRAGE)从细胞表面脱落,存在于人体循环中,并与心血管疾病有关。但其病理生理学调节和潜在机制尚不清楚。在血管内皮细胞特异性人类 RAGE 转基因小鼠中,循环中检测到人类 sRAGE,而 LPS 处理后其水平显著增加。这种增加之前是 TNF-α 水平的快速上升。TNF-α 治疗也显著增加了血清 sRAGE。在过表达 RAGE 的人微血管内皮细胞或人脐静脉内皮细胞中,TNF-α 显著诱导 RAGE 脱落,这依赖于 MMP9 和 ADAM10。TNF-α 刺激的 MMP9 表达完全依赖于 JNK 激活,其抑制作用部分有效抑制 TNF-α 诱导的 RAGE 脱落。相反,TNF-α 短暂诱导激活转录因子(ATF)4,这是未折叠蛋白反应(UPR)的主要组成部分,而 ATF4 的敲低则阻断了 TNF-α 刺激的 RAGE 脱落。ADAM10 的前体和激活形式的蛋白水平也因 ATF4 的敲低而降低,而 UPR 的其他成分,包括 XBP1 和 ATF6 的抑制,未能阻断 TNF-α 刺激的 RAGE 脱落。虽然内质网应激剂 thapsigargin 和 tunicamycin 诱导 ATF4 和 XBP-1 的表达显著且持续,但它们没有诱导 RAGE 脱落到与 TNF-α 相同的水平,表明 ATF4 是必要的,但不足以单独介导 TNF-α 介导的 RAGE 脱落。ATF4 抑制不影响 TNF-α 刺激的 MMP9 表达,而 JNK 活性的抑制不影响 ADAM10 的激活。因此,炎症级联反应包括 TNF-α 诱导的体内和体外内皮细胞 RAGE 脱落。JNK 和 ATF4 可能是调节 TNF-α 刺激的 RAGE 脱落的两个重要平台。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验