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Functional analysis of membrane TNF-α on activated T cells

膜TNF-α对活化T细胞的功能分析

基本信息

批准号：
10670417
负责人：
HORIUCHI Takahiko
金额：
$ 2.37万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670417/
关键词：
TNF-α E-selectin CD4+ T cells サイトカイン膜型TNF-α

项目摘要

The membrane tumor necrosis factor-α (TNF-α) is known to serve as a precursor of the soluble form of TNF-α. Although it has been reported the biological functions of the membrane TNF-α as a ligand, the reverse (outside-to-inside) signal transmitted through membrane TNF-α is poorly understood. We here report a novel function mediated by outside-to-inside signal via membrane TNF-α. Activation by anti-TNF-α antibody (Ab) against membrane TNF-α on HTLV-I-infected T cell line, MT-2, or PHA-activated normal human CD4+ T cells resulted in the induction of an adhesion molecule, E-selectin (CD62E), on the cells with the peak of 12 to 24 h, which was completely disappeared at 45 h. When wild-type or mutant membrane TNF-α (R78T/S79T) resistant to proteolytical cleavage was introduced into Jurkat or HeLa cells, E-selectin was induced by the treatment with anti-TNF-α Ab with the similar kinetics. Northern blot analysis and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed that the membrane TNF-α-mediated E-selectin expression was upregulated at the level of transcription. These results not only confirmed our previous findings of reverse signaling through membrane TNF-α, but also presented for the first time that E-selectin was inducible in cell types different from endothelial cells. It is strongly suggested that membrane TNF-α is a novel proinflammatory cell surface molecule that transmit bipolar signals in local inflammation.

已知膜肿瘤坏死因子-α（TNF-α）是可溶性TNF-α的前体。虽然已经报道了膜TNF-α作为配体的生物学功能，但是通过膜TNF-α传递的反向（由外向内）信号知之甚少。我们在这里报告了一个新的功能介导的由外到内的信号通过膜TNF-α。抗TNF-α抗体（Ab）激活HTLV-1感染的T细胞系MT-2或PHA激活的正常人CD 4 + T细胞，可诱导细胞表面粘附分子E-选择素（CD 62 E）的产生，在12 ~ 24 h达高峰，45 h完全消失。当将抗蛋白水解的野生型或突变型膜TNF-α（R78 T/S79 T）导入Jurkat或HeLa细胞中时，抗TNF-α Ab以相似的动力学诱导E-选择素。北方印迹分析和逆转录聚合酶链反应（RT-PCR）分析表明，TNF-α在转录水平上调了E-选择素的表达。这些结果不仅证实了我们以前的发现，通过膜TNF-α的反向信号，但也首次提出，E-选择素是诱导的细胞类型不同于内皮细胞。这强烈表明，膜TNF-α是一种新的促炎细胞表面分子，在局部炎症中传递双极信号。