Van Zee KJ, Kohno T, Fischer E, Rock CS, Moldawer LL, Lowry SF.. Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. Proc Natl Acad Sci USA 89: 4845-4849

Laboratory of Surgical Metabolism, New York Hospital-Cornell University Medical Center, NY 10021.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/1992; 89(11):4845-9. DOI: 10.1073/pnas.89.11.4845
Source: PubMed


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.

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Available from: Cosmo Rock, Apr 19, 2015
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    • "Including the level of soluble receptors with the early TNF-a response provided a more dynamic assessment of this early proinflammatory cytokine in mediating aspiration-induced ALI. TNFsRI in particular has been shown to play a crucial role in alveolar epithelial dysfunction after acid aspiration, while also blocking and attenuating the biologic effects of excessive TNF-a [43] [44]. This may help explain our observation of TNF-a levels at 5 h after low pH gastric aspiration, owing to a more pronounced cytoprotective response by TNFsRI in the high AGE-fed mice. "
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    • "Indeed, changes in serum levels of TNFR2 correlate significantly with renal transplant rejection [67] and renal injury in mice [44]. The soluble shed TNFR2, which is capable of binding TNF, may neutralize TNF-induced cytotoxicity and immune-reactivity thus downregulating inflammation in vivo and in vitro [60]. "
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    11/2013; 2013:821310. DOI:10.1155/2013/821310
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    • "TNF-α is a key inflammatory mediator in bacterial sepsis. It appears early following the event, initiating host response mechanisms, such as induction of other cytokines and fever 31-33. Virtually all cell types possess either sTNFRI or sTNFRII, or both, which mediate the vast range of the TNF-α effect. "
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