SEARCH:   Advanced

Blood, 15 December 2004, Vol. 104, No. 13, pp. 4071-4079. Prepublished online as a Blood First Edition Paper on August 24, 2004; DOI 10.1182/blood-2003-04-1290. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-04-1290v1 104/13/4071    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Pugin, J. Articles by Dunn-Siegrist, I. Search for Related Content PubMed PubMed Citation Articles by Pugin, J. Articles by Dunn-Siegrist, I. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Soluble MD-2 activity in plasma from patients with severe sepsis and septic shock Jérôme Pugin, Sabine Stern-Voeffray, Bruno Daubeuf, Michael A. Matthay, Greg Elson, and Irène Dunn-Siegrist From the Laboratory of the Division of Medical Intensive Care, Departments of Internal Medicine, Microbiology, and Molecular Medicine, University Hospital of Geneva, Geneva, Switzerland; the Faculty of Medicine, University Hospital of Geneva, Geneva, Switzerland; NovImmune S.A., Geneva, Switzerland; and the Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA. In this paper, we show that plasma from patients with severe sepsis and septic shock but not normal plasma supports lipopolysaccharide (LPS) activation of epithelial cells expressing Toll-like receptor 4 (TLR4). Recombinant soluble myeloid differentiation protein-2 (MD-2) complemented normal plasma and allowed LPS activation of epithelial cells to levels measured with "septic" plasma, whereas soluble MD-2-depleted plasma lost its effects. The same "MD-2 activity" was found in urine from a patient with septic shock and in lung edema fluids from patients with adult respiratory distress syndrome (ARDS). Recombinant soluble MD-2 enabled LPS-dependent activation of epithelial cells bearing TLR4. LPS-binding protein (LBP) and soluble CD14 increased the sensitivity of TLR4-expressing epithelial cells to LPS but were not able to mediate LPS activation of these cells in the absence of soluble MD-2. An anti-MD-2 monoclonal antibody blocked LPS activation of TLR4-expressing cells only in the presence of septic plasma or septic urine. These results suggest that septic plasma containing soluble MD-2 leaking into the extravascular space supports LPS activation of TLR4-expressing epithelial cells. We therefore propose that soluble MD-2 is an important mediator of organ inflammation during sepsis. (Blood. 2004;104:4071-4079) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Vasl, P. Prohinar, T. L. Gioannini, J. P. Weiss, and R. Jerala Functional Activity of MD-2 Polymorphic Variant Is Significantly Different in Soluble and TLR4-Bound Forms: Decreased Endotoxin Binding by G56R MD-2 and Its Rescue by TLR4 Ectodomain J. Immunol., May 1, 2008; 180(9): 6107 - 6115. [Abstract] [Full Text] [PDF] P. Tissieres, I. Dunn-Siegrist, M. Schappi, G. Elson, R. Comte, V. Nobre, and J. Pugin Soluble MD-2 is an acute-phase protein and an opsonin for Gram-negative bacteria Blood, February 15, 2008; 111(4): 2122 - 2131. [Abstract] [Full Text] [PDF] A. Teghanemt, P. Prohinar, T. L. Gioannini, and J. P. Weiss Transfer of Monomeric Endotoxin from MD-2 to CD14: CHARACTERIZATION AND FUNCTIONAL CONSEQUENCES J. Biol. Chem., December 14, 2007; 282(50): 36250 - 36256. [Abstract] [Full Text] [PDF] I. Dunn-Siegrist, O. Leger, B. Daubeuf, Y. Poitevin, F. Depis, S. Herren, M. Kosco-Vilbois, Y. Dean, J. Pugin, and G. Elson Pivotal Involvement of Fc{gamma} Receptor IIA in the Neutralization of Lipopolysaccharide Signaling via a Potent Novel Anti-TLR4 Monoclonal Antibody 15C1 J. Biol. Chem., November 30, 2007; 282(48): 34817 - 34827. [Abstract] [Full Text] [PDF] B. Daubeuf, J. Mathison, S. Spiller, S. Hugues, S. Herren, W. Ferlin, M. Kosco-Vilbois, H. Wagner, C. J. Kirschning, R. Ulevitch, et al. TLR4/MD-2 Monoclonal Antibody Therapy Affords Protection in Experimental Models of Septic Shock J. Immunol., November 1, 2007; 179(9): 6107 - 6114. [Abstract] [Full Text] [PDF] G. Elson, I. Dunn-Siegrist, B. Daubeuf, and J. Pugin Contribution of Toll-like receptors to the innate immune response to Gram-negative and Gram-positive bacteria Blood, February 15, 2007; 109(4): 1574 - 1583. [Abstract] [Full Text] [PDF] H. BOSSHART and M. HEINZELMANN Targeting Bacterial Endotoxin: Two Sides of a Coin Ann. N.Y. Acad. Sci., January 1, 2007; 1096(1): 1 - 17. [Abstract] [Full Text] [PDF] C. Nishitani, H. Mitsuzawa, H. Sano, T. Shimizu, N. Matsushima, and Y. Kuroki Toll-like Receptor 4 Region Glu24-Lys47 Is a Site for MD-2 Binding: IMPORTANCE OF CYS29 AND CYS40 J. Biol. Chem., December 15, 2006; 281(50): 38322 - 38329. [Abstract] [Full Text] [PDF] H. Mitsuzawa, C. Nishitani, N. Hyakushima, T. Shimizu, H. Sano, N. Matsushima, K. Fukase, and Y. Kuroki Recombinant Soluble Forms of Extracellular TLR4 Domain and MD-2 Inhibit Lipopolysaccharide Binding on Cell Surface and Dampen Lipopolysaccharide-Induced Pulmonary Inflammation in Mice J. Immunol., December 1, 2006; 177(11): 8133 - 8139. [Abstract] [Full Text] [PDF] T. Ruby, C. Whittaker, D. R. Withers, M. K. Chelbi-Alix, V. Morin, A. Oudin, J. R. Young, and R. Zoorob Transcriptional profiling reveals a possible role for the timing of the inflammatory response in determining susceptibility to a viral infection. J. Virol., September 1, 2006; 80(18): 9207 - 9216. [Abstract] [Full Text] [PDF] K. Miyake Invited review: Roles for accessory molecules in microbial recognition by Toll-like receptors Innate Immunity, August 1, 2006; 12(4): 195 - 204. [Abstract] [PDF] J.-M. Cavaillon and D. Annane Invited review: Compartmentalization of the inflammatory response in sepsis and SIRS Innate Immunity, June 1, 2006; 12(3): 151 - 170. [Abstract] [PDF] L. Romics Jr, G. Szabo, J. C. Coffey, J. H. Wang, and H. P. Redmond The Emerging Role of Toll-Like Receptor Pathways in Surgical Diseases Arch Surg, June 1, 2006; 141(6): 595 - 601. [Abstract] [Full Text] [PDF] A. Tuin, A. Huizinga-Van der Vlag, A.-M. M. A. van Loenen-Weemaes, D. K. F. Meijer, and K. Poelstra On the role and fate of LPS-dephosphorylating activity in the rat liver Am J Physiol Gastrointest Liver Physiol, February 1, 2006; 290(2): G377 - G385. [Abstract] [Full Text] [PDF] T. R. Martin and C. W. Frevert Innate Immunity in the Lungs Proceedings of the ATS, December 1, 2005; 2(5): 403 - 411. [Abstract] [Full Text] [PDF] A. Visintin, K. A. Halmen, E. Latz, B. G. Monks, and D. T. Golenbock Pharmacological Inhibition of Endotoxin Responses Is Achieved by Targeting the TLR4 Coreceptor, MD-2 J. Immunol., November 15, 2005; 175(10): 6465 - 6472. [Abstract] [Full Text] [PDF] D. R. Blais, S. G. Vascotto, M. Griffith, and I. Altosaar LBP and CD14 Secreted in Tears by the Lacrimal Glands Modulate the LPS Response of Corneal Epithelial Cells Invest. Ophthalmol. Vis. Sci., November 1, 2005; 46(11): 4235 - 4244. [Abstract] [Full Text] [PDF] S. R. Coats, T.-T. T. Pham, B. W. Bainbridge, R. A. Reife, and R. P. Darveau MD-2 Mediates the Ability of Tetra-Acylated and Penta-Acylated Lipopolysaccharides to Antagonize Escherichia coli Lipopolysaccharide at the TLR4 Signaling Complex J. Immunol., October 1, 2005; 175(7): 4490 - 4498. [Abstract] [Full Text] [PDF] R. S. Munford Invited review: Detoxifying endotoxin: time, place and person Innate Immunity, April 1, 2005; 11(2): 69 - 84. [Abstract] [PDF]

	Blood Online is supported in part by Genentech BioOncology and Biogen Idec
	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020