The C‐terminal region of tumor necrosis factor like weak inducer of apoptosis is required for interaction with advanced glycation end products
The C‐terminal region of tumor necrosis factor like weak inducer of apoptosis is required for interaction with advanced glycation end products
复制标题
肿瘤坏死因子的 C 末端区域（如弱凋亡诱导剂）是与晚期糖基化终产物相互作用所必需的
DOI：
10.1002/bab.1706
复制
发表时间：
2018
影响因子：
2.8
通讯作者：
Mori Shuji
中科院分区：
文献类型：
--
作者：
Watanabe Masahiro;Toyomura Takao;Wake Hidenori;Liu Keyue;Teshigawara Kiyoshi;Takahashi Hideo;Nishibori Masahiro;Mori Shuji
以前，我们发现内源性产生的促炎分子，晚期糖基化终产物(AGEs)，与肿瘤坏死因子样的弱凋亡诱导物(TWEY)相互作用，并减弱其免疫调节功能。在本研究中，为了阐明AGEs减弱TWEAM功能的机制，我们利用TWEAT缺失突变体寻找负责TWEINE-AGE相互作用的区域。对TWEY突变体和AGEs的下拉分析表明，这种相互作用需要TWEY的C末端一半，这是受体刺激所必需的区域。另一方面，N末端缺失突变体的AGE结合没有明显减少。此外，观察到在四分C末端半区通过双缺失适度减少了AGE结合，在该区域通过三次缺失显著减少了AGE结合。此外，全长TWEE刺激内皮EA.hy.926细胞中IL-8基因的表达，而三重缺失突变体失去了大部分这种活性，这表明TWEAGE相互作用部位与发挥TWEK正常功能所需的区域重叠。我们目前的发现可能有助于阐明TTWINE-AGE相互作用在预防和治疗年龄相关性炎症性疾病中的病理生理作用。
Previously, we found that endogenously produced pro‐inflammatory molecules, advanced glycation end products (AGEs), interact with tumor necrosis factor‐like weak inducer of apoptosis (TWEAK), and attenuate its immunomodulatory function. In the present study, to elucidate the mechanism by which AGEs attenuate TWEAK function, we searched for regions responsible for TWEAK–AGE interaction using TWEAK deletion mutants. Pull‐down assays with the TWEAK mutants and AGEs revealed that the C‐terminal half of TWEAK, which is the region essential for receptor stimulation, was required for this interaction. On the other hand, the N‐terminal deletion mutants did not exhibit a significant decrease in AGE binding. Moreover, a moderate decrease in the AGE binding by double‐deletion in quartered C‐terminal half regions and a substantial decrease by triple‐deletion in this region were observed. In addition, full‐length TWEAK stimulated IL‐8 gene expression in endothelial EA.hy.926 cells, whereas the triple‐deletion mutant lost much of this activity, suggesting that the TWEAK–AGE interaction sites overlap with the region needed to exert normal function of TWEAK. Our present findings may help to elucidate the pathophysiological roles of the TWEAK–AGE interaction for prevention and treatment of AGE‐related inflammatory diseases.