Function of the p55 tumor necrosis factor receptor "death domain" mediated by phosphatidylcholine-specific phospholipase C.
Function of the p55 tumor necrosis factor receptor "death domain" mediated by phosphatidylcholine-specific phospholipase C.
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DOI：
10.1084/jem.184.2.725
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发表时间：
1996-08-01
期刊：
影响因子：
--
通讯作者：
Krönke M
中科院分区：
文献类型：
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作者：
Machleidt T;Krämer B;Adam D;Neumann B;Schütze S;Wiegmann K;Krönke M
肿瘤坏死因子（TNF）是一种多效性炎症介质，与感染性休克等严重临床综合征的发病机制有关。我们已经研究了TNF-反应性磷脂酰胆碱特异性磷脂酶C（PC-PLC）对TNF的细胞毒性和促炎活性的作用。我们在这里表明，由所谓的p55 TNF受体的“死亡结构域”发出的细胞毒性信号与PC-PLC的激活有关。黄原酸酯三环癸烷-9-基（D 609）是一种特异性和选择性的PC-PLC抑制剂，它能阻断TNF对L929和Wehi 164细胞的细胞毒作用。在体内，D 609阻止了TNF处理小鼠肺血管中粘附分子的表达和伴随的白细胞浸润。更引人注目的是，D 609保护BALB/c小鼠免受TNF、脂多糖或葡萄球菌肠毒素B诱导的致死性休克。总之，这些发现意味着PC PLC作为一个重要的介质的致病作用的TNF，这表明PC PLC可能作为一个新的目标，抗炎TNF拮抗剂。
Tumor necrosis factor (TNF) is a pleiotropic mediator of inflammation that has been implicated in the pathogenesis of devastating clinical syndromes including septic shock. We have investigated the role of a TNF-responsive phosphatidylcholine-specific phospholipase C (PC-PLC) for the cytotoxic and proinflammatory activity of TNF. We show here that the cytotoxicity signaled for by the so-called "death domain" of the p55 TNF receptor is associated with the activation of PC-PLC. The xanthogenate tricyclodecan-9-yl (D609), a specific and selective inhibitor of PC-PLC, blocked the cytotoxic action of TNF on L929 and Wehi164 cells. In vivo, D609 prevented both adhesion molecule expression in the pulmonary vasculature and the accompanying leukocyte infiltration in TNF-treated mice. More strikingly, D609 protects BALB/c mice from lethal shock induced either by TNF, lipopolysaccharide, or staphylococcal enterotoxin B. Together these findings imply PC-PLC as an important mediator of the pathogenic action of TNF, suggesting that PC-PLC may serve as a novel target for anti-inflammatory TNF antagonists.