In vivo evidence for a functional role of both tumor necrosis factor (TNF) receptors and transmembrane TNF in experimental hepatitis
In vivo evidence for a functional role of both tumor necrosis factor (TNF) receptors and transmembrane TNF in experimental hepatitis
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DOI：
10.1002/eji.1830271119
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发表时间：
1997-11-01
影响因子：
5.4
通讯作者：
Grell, M
中科院分区：
文献类型：
--
作者：
Kusters, S;Tiegs, G;Grell, M
在伴刀豆球蛋白 A (Con A) 诱导的 CD4+ T 细胞依赖性小鼠实验性肝炎模型中，TNF 是细胞凋亡和坏死性肝损伤的中心介质，我们现在为 TNFR2 在这一病理生理过程中发挥重要的体内功能提供了证据。我们证明，肝毒性需要 TNFR1 和 TNFR2 的协同作用，因为缺乏任一受体的小鼠对 Con A 具有抗性。过表达人 TNFR2 的转基因小鼠的敏感性增强也表明了 TNFR2 对 Con A 诱导的肝炎的重要作用。通过两种 TNF 受体进行细胞毒性信号传导的配体是可溶性 TNF 的前体，即 TNF。 e.跨膜TNF 事实上，跨膜TNF足以介导肝损伤，因为缺乏野生型可溶性TNF但表达突变的不可分泌形式TNF的转基因小鼠会患上炎症性肝病。肿瘤坏死因子受体 1 (TNFR1) 对体内 TNF 功能的重要性已得到充分证明，而 TNFR2 的作用迄今为止仍不清楚。
In a model of concanavalin A (Con A)-induced, CD4(+) T cell-dependent experimental hepatitis in mice, in which TNF is a central mediator of apoptotic and necrotic liver damage, we now provide evidence for an essential in vivo function of TNFR2 in this pathophysiological process. We demonstrate that a cooperation of TNFR1 and TNFR2 is required for hepatotoxicity as mice deficient of either receptor were resistant against Con A. A significant role of TNFR2 for Con A-induced hepatitis is also shown by the enhanced sensitivity of transgenic mice overexpressing the human TNFR2. The ligand for cytotoxic signaling via both TNF receptors is the precursor of soluble TNF, i. e. transmembrane TNF Indeed, transmembrane TNF is sufficient to mediate hepatic damage, as transgenic mice deficient in wild-type soluble TNF but expressing a mutated nonsecretable form of TNF developed inflammatory liver disease. The significance of tumor necrosis factor receptor 1 (TNFR1) for TNF function in vivo is well documented, whereas the role of TNFR2 so far remains obscure.