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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4637-4645. Prepublished online as a Blood First Edition Paper on January 18, 2008; DOI 10.1182/blood-2007-11-126862. This Article Full Text (PDF) All Versions of this Article: blood-2007-11-126862v1 111/9/4637    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 Jain, V. Articles by Visintin, A. Search for Related Content PubMed PubMed Citation Articles by Jain, V. Articles by Visintin, A. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 30, 2007 Accepted January 16, 2008 Phagocytosis and intracellular killing of MD-2 opsonized Gram-negative bacteria depend on TLR4 signaling Vishal Jain, Annett Halle, Kristen A Halmen, Egil Lien, Marie Charrel-Dennis, Sanjay Ram, Douglas T Golenbock, and Alberto Visintin* Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, United States * Corresponding author; email: alberto.visintin{at}umassmed.edu. Both Toll-like receptor 4 (TLR4) and MD-2 deficient mice succumb to otherwise non-fatal Gram negative bacteria inocula, demonstrating the pivotal role played by these proteins in anti-bacterial defense in mammals. MD-2 is a soluble endogenous ligand for TLR4 and a receptor for lipopolysaccharide (LPS). LPS-bound MD-2 transmits an activating signal onto TLR4. In this report we show that both recombinant and endogenous soluble MD-2 bind tightly to the surface of live Gram-negative bacteria. As a consequence, MD-2 enhances cellular activation, bacterial internalization and intracellular killing, all in a TLR4 dependent manner. The enhanced internalization of MD-2 coated bacteria was not observed in macrophages expressing Lpsd, a signaling incompetent mutant form of TLR4, suggesting that the enhanced phagocytosis observed is dependent on signal transduction. The data confirms the notion that soluble MD-2 is a genuine opsonin which enhances pro-inflammatory opsonophagocytosis by bridging live Gram-negative bacteria to the LPS transducing complex. The presented results extend our understanding of the role of the TLR4/MD-2 signaling axis in bacterial recognition by phagocytes. 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] H. S. Oz, T. S. Chen, and M. Neuman Nutrition Intervention: A Strategy Against Systemic Inflammatory Syndrome JPEN J Parenter Enteral Nutr, July 1, 2009; 33(4): 380 - 389. [Abstract] [Full Text] [PDF] C. Moulakakis and C. Stamme Role of clathrin-mediated endocytosis of surfactant protein A by alveolar macrophages in intracellular signaling Am J Physiol Lung Cell Mol Physiol, March 1, 2009; 296(3): L430 - L441. [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] R. Lizundia, K.-S. Sauter, G. Taylor, and D. Werling Host species-specific usage of the TLR4-LPS receptor complex Innate Immunity, August 1, 2008; 14(4): 223 - 231. [Abstract] [PDF]

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