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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2122-2131. Prepublished online as a Blood First Edition Paper on December 4, 2007; DOI 10.1182/blood-2007-06-097782. This Article Full Text (PDF) All Versions of this Article: blood-2007-06-097782v1 111/4/2122    most recent Alert me when this article is cited Alert me if a correction is posted 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 Tissieres, P. Articles by Pugin, J. Search for Related Content PubMed PubMed Citation Articles by Tissieres, P. Articles by Pugin, J. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 25, 2007 Accepted November 29, 2007 Soluble MD-2 is an acute phase protein and an opsonin for Gram-negative bacteria Pierre Tissieres, Irene Dunn-Siegrist, Michela Schappi, Greg Elson, Rachel Comte, Vandack Nobre, and Jerome Pugin* Department of Anesthesiology, Pharmacology and Intensive Care, University Hospitals of Geneva, Geneva, Switzerland Department of Pediatrics, Children's Hospital of Geneva, Geneva, Switzerland NovImmune SA, Geneva, Switzerland * Corresponding author; email: jerome.pugin{at}medecine.unige.ch. MD-2 is a lipopolysaccharide (LPS)-binding protein usually co-expressed with and binding to Toll-like receptor 4 (TLR4), conferring LPS responsiveness of immune cells. MD-2 is also found as a soluble protein. Soluble MD-2 (sMD-2) levels are markedly elevated in plasma from patients with severe infections, and in other fluids from inflamed tissues. We show that sMD-2 is a type II acute phase protein (APP). Soluble MD-2 mRNA and protein levels are up-regulated in mouse liver after the induction of an acute phase response. It is secreted by human hepatocytic cells and up-regulated by interleukin-6. Soluble MD-2 binds to Gram-negative but not Gram-positive bacteria, and sMD-2 secreted by hepatocytic cells is an essential co-factor for the activation of TLR4-expressing cells by Gram-negative bacteria. Soluble MD-2 opsonization of Gram-negative bacteria accelerates and enhances phagocytosis, principally by polymorphonuclear neutrophils. In summary, our results demonstrate that sMD-2 is a newly recognized type II acute phase reactant, an opsonin for Gram-negative bacteria, and a co-factor essential for the activation of TLR4-expressing cells. This suggests that sMD-2 plays a key role in the host innate immune response to Gram-negative infections. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. Tissieres, T. Araud, A. Ochoda, G. Drifte, I. Dunn-Siegrist, and J. Pugin Cooperation between PU.1 and CAAT/Enhancer-binding Protein {beta} Is Necessary to Induce the Expression of the MD-2 Gene J. Biol. Chem., September 25, 2009; 284(39): 26261 - 26272. [Abstract] [Full Text] [PDF] P. Gross, K. Brandl, C. Dierkes, J. Scholmerich, B. Salzberger, T. Gluck, and W. Falk Lipopolysaccharide-Trap-Fc, a Multifunctional Agent To Battle Gram-Negative Bacteria Infect. Immun., July 1, 2009; 77(7): 2925 - 2931. [Abstract] [Full Text] [PDF] O. Sandanger, L. Ryan, J. Bohnhorst, A.-C. Iversen, H. Husebye, O. Halaas, L. Landro, P. Aukrust, S. S. Froland, G. Elson, et al. IL-10 Enhances MD-2 and CD14 Expression in Monocytes and the Proteins Are Increased and Correlated in HIV-Infected Patients J. Immunol., January 1, 2009; 182(1): 588 - 595. [Abstract] [Full Text] [PDF] V. Jain, A. Halle, K. A. Halmen, E. Lien, M. Charrel-Dennis, S. Ram, D. T. Golenbock, and A. Visintin Phagocytosis and intracellular killing of MD-2 opsonized Gram-negative bacteria depend on TLR4 signaling Blood, May 1, 2008; 111(9): 4637 - 4645. [Abstract] [Full Text] [PDF]

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