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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3655-3662. Prepublished online as a Blood First Edition Paper on January 11, 2005; DOI 10.1182/blood-2004-07-2523. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-07-2523v1 105/9/3655    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 Hopkins, P. A. Articles by Sriskandan, S. Search for Related Content PubMed PubMed Citation Articles by Hopkins, P. A. Articles by Sriskandan, S. Related Collections Immunobiology Phagocytes Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Superantigen recognition by HLA class II on monocytes up-regulates toll-like receptor 4 and enhances proinflammatory responses to endotoxin Philip A. Hopkins, John D. Fraser, Alison C. Pridmore, Hugh H. Russell, Robert C. Read, and Shiranee Sriskandan From the Department of Infectious Diseases, Imperial College, London, United Kingdom; the Division of Molecular Biology, University of Auckland, New Zealand; and the Department of Genomic Medicine, University of Sheffield, Sheffield, United Kingdom. The devastating systemic effects of bacterial superantigens may be explained by powerful proinflammatory synergy with lipopolysaccharide (LPS). However, the mechanism underlying this phenomenon remains unclear and has never been investigated in humans. Specifically, there is no known link between superantigen-induced immune effects and the pattern recognition of LPS at toll-like receptor 4 (TLR4). Here we show that bacterial superantigens induce rapid transcription and increased membrane expression of TLR4 in primary human monocytes by ligation of major histocompatibility complex (MHC) class II. We also demonstrate that superantigens are solely responsible for monocyte TLR4 up-regulation induced by products from Gram-positive bacteria. In parallel with enhanced TLR4 expression, priming of purified monocytes or mixed peripheral blood mononuclear cells with superantigens significantly enhanced the induction of proinflammatory cytokines by known TLR4 ligands. Staphylococcal enterotoxin A constructs containing targeted mutations were used to demonstrate a requirement for MHC class II ligation in both TLR4 up-regulation and enhanced responses to endotoxin. In contrast to results from animal models, superantigen-endotoxin interaction was not dependent on T-cell receptor ligation by superantigen or interferon gamma production. Pattern recognition of bacterial superantigens by MHC class II receptors may exacerbate the proinflammatory response of monocytes to Gram-negative infection or endotoxin by up-regulation of TLR4. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: F. Zapata-Gonzalez, F. Rueda, J. Petriz, P. Domingo, F. Villarroya, A. de Madariaga, and J. C. Domingo 9-cis-Retinoic Acid (9cRA), a Retinoid X Receptor (RXR) Ligand, Exerts Immunosuppressive Effects on Dendritic Cells by RXR-Dependent Activation: Inhibition of Peroxisome Proliferator-Activated Receptor {gamma} Blocks Some of the 9cRA Activities, and Precludes Them to Mature Phenotype Development J. Immunol., May 15, 2007; 178(10): 6130 - 6139. [Abstract] [Full Text] [PDF] O. Dauwalder, D. Thomas, T. Ferry, A.-L. Debard, C. Badiou, F. Vandenesch, J. Etienne, G. Lina, and G. Monneret Comparative inflammatory properties of staphylococcal superantigenic enterotoxins SEA and SEG: implications for septic shock J. Leukoc. Biol., October 1, 2006; 80(4): 753 - 758. [Abstract] [Full Text] [PDF]

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