Recombinant soluble tumor necrosis factor receptor proteins protect mice from lipopolysaccharide‐induced lethality

Lesslauer, Werner; Tabuchi, Hisahiro; Gentz, Reiner; Brockhaus, Manfred; Schlaeger, Ernst Juergen; Grau, Georges E.; Piguet, P F; Pointaire, Pascal; Vassalli, Pierre; Loetscher, H

doi:10.1002/eji.1830211134

Cited by 230 publications

(90 citation statements)

References 20 publications

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“…48 Therapeutic strategies for the treatment of fulminant hepatic failure have been examined using animal models. These approaches include: 1) inhibition of coupling between extracellular death factors (e.g., Fas ligand and TNF-␣) and their receptors, using a soluble receptor 17,49 or monoclonal antibodies 50 ; and, currently, 2) inhibition of intracellular apoptotic signals, using a specific inhibitor for caspase proteases. 51 We describe here a distinct strategy for the treatment of fulminant hepatic failure, using HGF, a physiological hepatotrophic factor.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice

et al. 1999

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Sepsis and endotoxemia are involved in the development of fulminant hepatic failure, the prognosis of which is extremely poor and the mortality is high, with no available effective therapy. Here, we report that hepatocyte growth factor (HGF) exerts potent antiapoptotic effects in vivo and effectively prevents endotoxin‐induced fulminant hepatic failure in mice. The animals were intraperitoneally injected three times with 120 μg human recombinant HGF or saline 6 hours and 30 minutes before and 3 hours after an intraperitoneal injection of lipopolysaccharide (LPS) and d ‐galactosamine (GalN). Administration of LPS + GalN, without HGF, rapidly led to massive hepatocyte apoptosis and severe liver injury, and all mice died of hepatic failure within 8 hours. In contrast, administration of human recombinant HGF strongly suppressed extensive progress of hepatocyte apoptosis and the liver injury induced by LPS + GalN, and 75% of the HGF‐treated mice survived. Moreover, HGF strongly induced Bcl‐xL expression and blocked apoptotic signal transduction upstream of CPP32 (caspase‐3) in the liver, thereby leading to inhibition of massive hepatocyte apoptosis. We suggest that HGF may well have the potential to prevent fulminant hepatic failure, at least through its potent antiapoptotic action.

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Section: Discussionmentioning

confidence: 99%

Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice

et al. 1999

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“…Apparently, this inhibitory system is in many cases insufficient to prevent the lethal consequences of high blood concentrations ofTNF. Increasing the levels ofsTNFRs by exogenous administration of recombinant or chimeric forms of those proteins may therefore prove to be beneficial for the outcome of sepsis [17,32,33].…”

Section: Discussionmentioning

confidence: 99%

Release of Soluble Receptors for Tumor Necrosis Factor in Clinical Sepsis and Experimental Endotoxemia

Poll

Jansen²,

Leenen³

et al. 1993

Journal of Infectious Diseases

115

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To assess the role of tumor necrosis factor (TNF) in the appearance of soluble TNF receptors (sTNFRs), 20 consecutive patients with a clinical diagnosis of sepsis were studied as were 7 chimpanzees after administration of endotoxin (4 ng/kg) with or without pentoxifylline. The patients had markedly elevated serum levels of sTNFR-p55 and sTNFR-p75 compared with healthy controls (P < .0001 for both receptors). The levels of both soluble receptors correlated with simultaneously measured immunoreactive TNF concentrations (p55: r = .63, P < .01; p75: r = .69, P < .001). In the chimpanzees, endotoxin induced subsequent rises in the serum concentrations ofTNF and sTNFRs. Although pentoxifylline reduced the TNF response to intravenous endotoxin to 20% (P < .05), the appearance of sTNFRs was only moderately inhibited (sTNFRp55 to 79% on average, P < .05; sTNFR-p75 to 77%, P = .12). These results indicate that TNF either does not play an important role in the appearance of sTNFRs in systemic infection or that a small amount of TNF remaining in the circulation after some bacterial challenges is sufficient to preserve the secretion of its soluble receptors.Sepsis is a syndrome characterized by hypotension, vascular leakage, and failure of multiple organs. Tumor necrosis factor (TNF) is an important factor for initiation ofthe septic syndrome [1 ]. Massive induction ofTNF synthesis, resulting in high concentrations of the protein in the circulation, is a prerequisite for the development of shock and multiple organ failure in experimental sepsis in animals [2]. In patients with sepsis, the extent of systemic TNF release correlates strongly with mortality rates [3,4]. Administration of TNF to animals or humans reproduces many of the features of septicemia [5,6]. Recently, naturally occurring inhibitors of TNF activity have been found in the urine of normal individuals and febrile patients and in the serum of patients with renal insufficiency [7][8][9][10][11]. These host mediators, originally termed TNF-binding proteins, have subsequently been identified as the soluble extracellular domains of the 55-and 75-kDa membrane-bound TNF receptors [12][13][14][15][16]. Soluble

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“…Recently, several reports describe the 'in viva' use of soluble recombinant receptors as antagonist of the corresponding cytokines (i.e. IFN-y receptor, [18,19]; IL4 receptor, [20]; IL1 receptor, [21]; TNF receptor, [22]) supporting the hypothesis that a soluble improved Fc&RI, capable of efficiently competing the natural one, could be of great therapeutic interest.…”

Section: Binding Of Phage Feandri To Igementioning

confidence: 99%

Receptor phage

Scarselli¹,

Esposito²,

Traboni³

1993

FEBS Letters

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In this paper we demonstrate that phage display technology is a suitable system for studying the interaction between the high-affinity receptor for IgE (FcsRI) and IgE. The a subunit extracellular domains of the human receptor were expressed on the surface of filamentous phage Ml3 fused to the carboxyl-terminal part of the gene III protein @III). Two constructs were made, the first with both the Ig-like domains of the receptor a chain and the second with only the C-terminal domain. The fusion genes were cloned in a phagemid vector to display monovalently the receptor on the phage surface. Our results indicate that the a receptor expressed on the phage is able to interact with IgE as demonstrated by an ELISA assay. In addition, by using the same system, we show that a single domain of the a receptor is sufficient for the interaction with IgE although with a binding afIinity lower than that of the two-domain receptor.Fc.sRI; Phage display; Receptor-immunoglobulin interaction

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Recombinant soluble tumor necrosis factor receptor proteins protect mice from lipopolysaccharide‐induced lethality

Cited by 230 publications

References 20 publications

Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice

Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice

Release of Soluble Receptors for Tumor Necrosis Factor in Clinical Sepsis and Experimental Endotoxemia

Receptor phage

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