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-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.