TUMOR-NECROSIS-FACTOR SOLUBLE RECEPTORS CIRCULATE DURING EXPERIMENTAL AND CLINICAL INFLAMMATION AND CAN PROTECT AGAINST EXCESSIVE TUMOR-NECROSIS-FACTOR-ALPHA INVITRO AND INVIVO
TUMOR-NECROSIS-FACTOR SOLUBLE RECEPTORS CIRCULATE DURING EXPERIMENTAL AND CLINICAL INFLAMMATION AND CAN PROTECT AGAINST EXCESSIVE TUMOR-NECROSIS-FACTOR-ALPHA INVITRO AND INVIVO
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DOI：
10.1073/pnas.89.11.4845
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发表时间：
1992-06-01
影响因子：
11.1
通讯作者：
LOWRY, SF
中科院分区：
文献类型：
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作者：
VANZEE, KJ;KOHNO, T;LOWRY, SF
肿瘤坏死因子-α（TNF-α）是脓毒症和感染全身反应的主要介质，当过量存在时可能对生物体有害。在这里，我们报告说，两种类型的自然发生的可溶性TNF受体（sTNFR-I和sTNFR-II）循环在人类实验性内毒素血症和重症患者，并证明他们中和TNF-α诱导的细胞毒性和免疫反应在体外。利用区分总sTNFR-I和不与TNF-α结合的sTNFR-I的免疫测定，我们表明sTNFR-I-TNF-α复合物即使在没有可检测到的游离TNF-α的情况下也可以循环。为了研究sTNFR-I的治疗可能性，将重组蛋白给予具有致死性菌血症的非人灵长类动物，发现其减弱血流动力学崩溃和细胞因子诱导。我们的结论是可溶性受体TNF-α诱导炎症和循环水平足以阻止在非致死性感染中观察到的TNF-α水平相关的体外细胞毒性。施用sTNFR-I可以预防由在致死性脓毒症中观察到的过度TNF-α产生引起的不良病理学后遗症。
Tumor necrosis factor-alpha (TNF-alpha), a primary mediator of systemic responses to sepsis and infection, can be injurious to the organism when present in excessive quantities. Here we report that two types of naturally occurring soluble TNF receptors (sTNFR-I and sTNFR-II) circulate in human experimental endotoxemia and in critically ill patients and demonstrate that they neutralize TNF-alpha-induced cytotoxicity and immunoreactivity in vitro. Utilizing immunoassays that discriminate between total sTNFR-I and sTNFR-I not bound to TNF-alpha, we show that sTNFR-I-TNF-alpha complexes may circulate even in the absence of detectable free TNF-alpha. To investigate the therapeutic possibilities of sTNFR-I, recombinant protein was administered to nonhuman primates with lethal bacteremia and found to attenuate hemodynamic collapse and cytokine induction. We conclude that soluble receptors for TNF-alpha are inducible in inflammation and circulate at levels sufficient to block the in vitro cytotoxicity associated with TNF-alpha levels observed in nonlethal infection. Administration of sTNFR-I can prevent the adverse pathologic sequelae caused by the exaggerated TNF-alpha production observed in lethal sepsis.