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Functional analyses for transmembrane TNF-alpha

跨膜 TNF-α 的功能分析

基本信息

批准号：
17591048
负责人：
HORIUCHI Takahiko
金额：
$ 2.24万
依托单位：
KYUSHU UNIVERCITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591048/
关键词：
Cytokine anti-TNF therapy rheumatoid arthritis apoptosis cell-cycle arrest TNF シグナル伝達

项目摘要

TNF-alpha antagonists are the center of attention for their dramatic clinical efficacy in active chronic inflammatory diseases. In rheumatoid arthritis, both infliximab (chimeric anti-TNF-alpha antibody), adalimumab (humanized anti-TNF-alpha antibody) and etanercept (p75 TNF-alpha receptor fusion protein) are highly effective, while in Crohn's disease, only infliximab and adalimumab can induce clinical remission. As the differential clinical efficacy was likely to be caused by biological effects other than mere neutralization of soluble TNF-alpha, we here investigated reverse signaling through transmembrane TNF-alpha. mTNF induced by infliximab was analysed by cDNA array in the assay system using mTNF-expressing Jurkat T cells.Cytoplasmic serine residues at positions 2, 5 and 27 of mTNF were sequentially substituted to alanine by site-directed mutagenesis. Infliximab-induced apoptosis and cell cycle arrest were completely abrogated by substitution of all of these three cytoplasmic serine residues. In this study, we revealed that novel biological effects induced by infliximab and etanercept were mediated by reverse signaling of mTNF, which might explain the differential clinical efficacy of these anti-TNF-alpha. agents. We also clarified that cytoplasmic serine residues were critical for the signal transduction through mTNF.

TNF-α拮抗剂因其在活动性慢性炎性疾病中的显著临床疗效而成为关注的中心。在类风湿性关节炎中，英夫利西单抗（嵌合抗TNF-α抗体）、阿达木单抗（人源化抗TNF-α抗体）和依那西普（p75 TNF-α受体融合蛋白）均高度有效，而在克罗恩病中，只有英夫利西单抗和阿达木单抗可诱导临床缓解。由于不同的临床疗效可能是由生物学效应引起的，而不仅仅是可溶性TNF-α的中和，因此我们在此研究了通过跨膜TNF-α的反向信号传导。用cDNA芯片分析了英夫利西单抗诱导的mTNF，并将mTNF的2、5、27位丝氨酸突变为丙氨酸。英夫利昔单抗诱导的细胞凋亡和细胞周期停滞完全废除了所有这三个细胞质丝氨酸残基的取代。在这项研究中，我们发现英夫利西单抗和依那西普诱导的新的生物学效应是由mTNF的反向信号传导介导的，这可能解释了这些抗TNF-α的差异临床疗效。剂.我们还阐明了细胞质丝氨酸残基是通过mTNF的信号转导的关键。