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.

Abstract

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.

Elevation of plasma-soluble tumour necrosis factor receptors (TNF-R) in sarcoidosis

“…Girardin et al [29] have shown that the ratio of TNF-to sTNF-R in serum from patients with severe meningococcaemia correlated with clinical outcome. In addition, protective effects of sTNF-R in sepsis [34,35] and inhibitory effects of sTNF-R against pulmonary fibrosis in the animal model [36] have been demonstrated. These previous results indicated that sTNF-R may contribute to regulating TNF--mediated disease.…”

“…The elevation of sTNF-R in serum/plasma and biological fluids reflecting a variety of inflammatory disorders has been shown in several diseases [24][25][26][27][28][29][30][31]. In addition, the specific inhibitory effects of sTNF-R on TNF-activities [32,33], the protective effects of sTNF-R in animal models of sepsis [34,35] and the inhibitory effects of sTNF-R against the animal model of pulmonary fibrosis [36] have been shown. Although TNF-has been suggested to play a role in the pathogenesis of sarcoidosis, plasma levels of sTNF-R have not been determined.…”

TNF-α and IFN-γ Regulate Expression and Function of the Fas System in the Seminiferous Epithelium

“…Moreover, soluble isoforms of cell-surface receptors regulate receptor function in a number of biological systems (27,28). Fas and FasL proteins can also occur both as cell-surface and soluble proteins, with the soluble form of Fas (sFas) being generated by alternative mRNA splicing (29,30), whereas the soluble form of FasL (sFasL) is produced through the proteolytic cleavage of the membrane-bound receptor (31).…”

TNF-Induced Shedding of TNF Receptors in Human Polymorphonuclear Leukocytes: Role of the 55-kDa TNF Receptor and Involvement of a Membrane-Bound and Non-Matrix Metalloproteinase

“…The released receptors, in turn, depending on their concentration relative to that of TNF, have been proposed either to compete with their membrane-bound counterparts and limit TNF bioavailability (17) or to stabilize the ligand thus enhancing TNF signaling (18).…”