Protective effect of 55- but not 75-kD soluble tumor necrosis factor receptor-immunoglobulin G fusion proteins in an animal model of gram- negative sepsis

doi:10.1084/jem.180.6.2173

This Article

	Full Text (PDF, 744K)
	Alert me when this article is cited
	Citation Map

Services

	Email this article
	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new content in the JEM
	Download to citation manager

Citing Articles

	Citing Articles via HighWire
	Citing Articles via CrossRef
	Citing Articles via Google Scholar

Google Scholar

	Articles by Evans, T. J.
	Articles by Cohen, J.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Evans, T. J.
	Articles by Cohen, J.


Social Bookmarking

	What's this?

ARTICLES

Protective effect of 55- but not 75-kD soluble tumor necrosis factor receptor-immunoglobulin G fusion proteins in an animal model of gram- negative sepsis

TJ Evans, D Moyes, A Carpenter, R Martin, H Loetscher, W Lesslauer and J Cohen
Department of Infectious Diseases and Bacteriology, Royal Postgraduate Medical School, London, UK.

The aim of this study was to compare the ability of both a 55- and 75- kD soluble tumor necrosis factor receptor immunoglobulin G fusion protein (sTNFR-IgG) in protecting against death in a murine model of gram-negative sepsis. Pretreatment with 250 micrograms of the p75 construct delayed but did not avert death in this model, reducing peak bioactive TNF-alpha levels after infection from 76.4 ng ml-1 in control mice to 4.7 ng ml-1 in the treated group (p < 0.05, two-sample t test). However, these low levels of bioactive TNF-alpha persisted in the p75 fusion protein-treated animals compared with the controls and were sufficient to mediate delayed death. In contrast, pretreatment with 200 micrograms of the p55 sTNFR-IgG gave excellent protection against death with complete neutralization of circulating TNF. Studies of the binding of TNF-alpha with the soluble TNFR fusion proteins showed that the p75 fusion construct exchanges bound TNF-alpha about 50-100-fold faster than the p55 fusion protein. Thus, although both fusion proteins in equilibrium bind TNF-alpha with high affinity, the TNF-alpha p55 fusion protein complex is kinetically more stable than the p75 fusion construct, which thus acts as a TNF carrier. The persistent release of TNF-alpha from the p75 fusion construct limits its therapeutic effect in this model of sepsis.
Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Add to Reddit Reddit Add to Technorati Technorati What's this?

This article has been cited by other articles:

Hori, M., Nishida, K. (2008). Oxidative stress and left ventricular remodelling after myocardial infarction. Cardiovasc Res 0: cvn335v2-8 [Abstract] [Full Text]
Adriaansen, J, Khoury, M, de Cortie, C J, Fallaux, F J, Bigey, P, Scherman, D, Gould, D J, Chernajovsky, Y, Apparailly, F, Jorgensen, C, Vervoordeldonk, M J B M, Tak, P P (2007). Reduction of arthritis following intra-articular administration of an adeno-associated virus serotype 5 expressing a disease-inducible TNF-blocking agent. Ann Rheum Dis 66: 1143-1150 [Abstract] [Full Text]
Cavadini, G., Petrzilka, S., Kohler, P., Jud, C., Tobler, I., Birchler, T., Fontana, A. (2007). From the Cover: TNF-{alpha} suppresses the expression of clock genes by interfering with E-box-mediated transcription. Proc. Natl. Acad. Sci. USA 104: 12843-12848 [Abstract] [Full Text]
Monden, Y., Kubota, T., Tsutsumi, T., Inoue, T., Kawano, S., Kawamura, N., Ide, T., Egashira, K., Tsutsui, H., Sunagawa, K. (2007). Soluble TNF receptors prevent apoptosis in infiltrating cells and promote ventricular rupture and remodeling after myocardial infarction. Cardiovasc Res 73: 794-805 [Abstract] [Full Text]
Rogers, K. A., Scinicariello, F., Attanasio, R. (2006). IgG Fc Receptor III Homologues in Nonhuman Primate Species: Genetic Characterization and Ligand Interactions. J. Immunol. 177: 3848-3856 [Abstract] [Full Text]
Nowlan, M. L., Drewe, E., Bulsara, H., Esposito, N., Robins, R. A., Tighe, P. J., Powell, R. J., Todd, I. (2006). Systemic cytokine levels and the effects of etanercept in TNF receptor-associated periodic syndrome (TRAPS) involving a C33Y mutation in TNFRSF1A. Rheumatology (Oxford) 45: 31-37 [Abstract] [Full Text]
Mann, D. L., McMurray, J. J.V., Packer, M., Swedberg, K., Borer, J. S., Colucci, W. S., Djian, J., Drexler, H., Feldman, A., Kober, L., Krum, H., Liu, P., Nieminen, M., Tavazzi, L., van Veldhuisen, D. J., Waldenstrom, A., Warren, M., Westheim, A., Zannad, F., Fleming, T. (2004). Targeted Anticytokine Therapy in Patients With Chronic Heart Failure: Results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 109: 1594-1602 [Abstract] [Full Text]
Sato, T. A., Keelan, J. A., Mitchell, M. D. (2003). Critical Paracrine Interactions Between TNF-{alpha} and IL-10 Regulate Lipopolysaccharide-Stimulated Human Choriodecidual Cytokine and Prostaglandin E2 Production. J. Immunol. 170: 158-166 [Abstract] [Full Text]
Mann, D. L. (2002). Inflammatory Mediators and the Failing Heart: Past, Present, and the Foreseeable Future. Circ. Res. 91: 988-998 [Abstract] [Full Text]
Krippner-Heidenreich, A., Tubing, F., Bryde, S., Willi, S., Zimmermann, G., Scheurich, P. (2002). Control of Receptor-induced Signaling Complex Formation by the Kinetics of Ligand/Receptor Interaction. J. Biol. Chem. 277: 44155-44163 [Abstract] [Full Text]
Eichacker, P. Q., Parent, C., Kalil, A., Esposito, C., Cui, X., Banks, S. M., Gerstenberger, E. P., Fitz, Y., Danner, R. L., Natanson, C. (2002). Risk and the Efficacy of Antiinflammatory Agents: Retrospective and Confirmatory Studies of Sepsis. Am. J. Respir. Crit. Care Med. 166: 1197-1205 [Abstract] [Full Text]
Scallon, B., Cai, A., Solowski, N., Rosenberg, A., Song, X.-Y., Shealy, D., Wagner, C. (2002). Binding and Functional Comparisons of Two Types of Tumor Necrosis Factor Antagonists. J. Pharmacol. Exp. Ther. 301: 418-426 [Abstract] [Full Text]
Ballard-Croft, C., White, D. J., Maass, D. L., Hybki, D. P., Horton, J. W. (2001). Role of p38 mitogen-activated protein kinase in cardiac myocyte secretion of the inflammatory cytokine TNF-{alpha}. Am. J. Physiol. Heart Circ. Physiol. 280: H1970-H1981 [Abstract] [Full Text]
Jin, L., Raymond, D. P., Crabtree, T. D., Pelletier, S. J., Houlgrave, C. W., Pruett, T. L., Sawyer, R. G. (2000). Enhanced Murine Macrophage TNF Receptor Shedding by Cytosine-Guanine Sequences in Oligodeoxynucleotides. J. Immunol. 165: 5153-5160 [Abstract] [Full Text]
Selmaj, K. W (2000). Tumour necrosis factor and anti-tumour necrosis factor approach to inflammatory demyelinating diseases of the central nervous system. Ann Rheum Dis 59: i94-102 [Full Text]
Opal, S. M., DePalo, V. A. (2000). Anti-Inflammatory Cytokines. Chest 117: 1162-1172 [Abstract] [Full Text]
Quattrocchi, E., Walmsley, M., Browne, K., Williams, R. O., Marinova-Mutafchieva, L., Buurman, W., Butler, D. M., Feldmann, M. (1999). Paradoxical Effects of Adenovirus-Mediated Blockade of TNF Activity in Murine Collagen-Induced Arthritis. J. Immunol. 163: 1000-1009 [Abstract] [Full Text]
van der Poll, T., Endert, E., Coyle, S. M., Agosti, J. M., Lowry, S. F. (1999). Neutralization of TNF does not influence endotoxininduced changes in thyroid hormone metabolism in humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 276: R357-R362 [Abstract] [Full Text]
Richter, W. F., Gallati, H., Schiller, C.-D. (1999). Animal Pharmacokinetics of the Tumor Necrosis Factor Receptor-Immunoglobulin Fusion Protein Lenercept and Their Extrapolation to Humans. Drug Metab. Dispos. 27: 21-25 [Abstract] [Full Text]
Smith, S., Skerrett, S. J., Chi, E. Y., Jonas, M., Mohler, K., Wilson, C. B. (1998). The locus of tumor necrosis factor-alpha action in lung inflammation.. Am. J. Respir. Cell Mol. Bio. 19: 881-891 [Abstract] [Full Text]
Chirinos-Rojas, C. L., Steward, M. W., Partidos, C. D. (1998). A Peptidomimetic Antagonist of TNF-{alpha}-Mediated Cytotoxicity Identified from a Phage-Displayed Random Peptide Library. J. Immunol. 161: 5621-5626 [Abstract] [Full Text]
Ksontini, R., MacKay, S. L. D., Moldawer, L. L. (1998). Revisiting the Role of Tumor Necrosis Factor {alpha} and the Response to Surgical Injury and Inflammation. Arch Surg 133: 558-567 [Abstract] [Full Text]
Miotla, J. M., Teixeira, M. M., Hellewell, P. G. (1998). Suppression of Acute Lung Injury in Mice by an Inhibitor of Phosphodiesterase Type 4�. Am. J. Respir. Cell Mol. Bio. 18: 411-420 [Abstract] [Full Text]
Meldrum, D. R. (1998). Tumor necrosis factor in the heart. Am. J. Physiol. Regul. Integr. Comp. Physiol. 274: R577-R595 [Abstract] [Full Text]
Grell, M., Wajant, H., Zimmermann, G., Scheurich, P. (1998). The type 1�receptor (CD120a) is the high-affinity receptor for soluble tumor�necrosis�factor. Proc. Natl. Acad. Sci. USA 95: 570-575 [Abstract] [Full Text]
van der Poll, T., Coyle, S. M., Levi, M., Jansen, P. M., Dentener, M., Barbosa, K., Buurman, W. A., Hack, C. E., ten Cate, J. W., Agosti, J. M., Lowry, S. F. (1997). Effect of a Recombinant Dimeric Tumor Necrosis Factor Receptor on Inflammatory Responses to Intravenous Endotoxin in Normal Humans. Blood 89: 3727-3734 [Abstract] [Full Text]
Whiteley, M. S., Glauser, M.-P., Cohen, J., Fisher, C. J., Agosti, J. M., Opal, S. M. (1996). Tumor Necrosis Factor Receptor:Fc Fusion Protein in Septic Shock. NEJM 335: 1607-1609 [Full Text]
Kalb, A., Bluethmann, H., Moore, M. W., Lesslauer, W. (1996). Tumor Necrosis Factor Receptors (Tnfr) in Mouse Fibroblasts Deficient in Tnfr1 or Tnfr2 are Signaling Competent and Activate the Mitogen-activated Protein Kinase Pathway with Differential Kinetics. J. Biol. Chem. 271: 28097-28104 [Abstract] [Full Text]
Fisher, C. J., Agosti, J. M., Opal, S. M., Lowry, S. F., Balk, R. A., Sadoff, J. C., Abraham, E., Schein, R. M.H., Benjamin, E., The Soluble TNF Receptor Sepsis Study Group, (1996). Treatment of Septic Shock with the Tumor Necrosis Factor Receptor:Fc Fusion Protein. NEJM 334: 1697-1702 [Abstract] [Full Text]
Knaus, W.A., Wagner, D.P., Sun, X., Harrell, F.E. JR, Hedstrom, J.S. (1995). Risk assessment in recent clinical trials in sepsis/SIRS: lessons learned and future directions. Innate Immunity 2: 169-175 [Abstract]