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Blood, 15 September 2007, Vol. 110, No. 6, pp. 1970-1981. Prepublished online as a Blood First Edition Paper on June 4, 2007; DOI 10.1182/blood-2006-09-044776. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-09-044776v1 110/6/1970    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 Ivanov, S. Articles by Chu, W.-M. Search for Related Content PubMed PubMed Citation Articles by Ivanov, S. Articles by Chu, W.-M. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA Stanimir Ivanov1, Ana-Maria Dragoi1, Xin Wang1, Corrado Dallacosta2, Jennifer Louten1, Giovanna Musco2, Giovanni Sitia2, George S. Yap1, Yinsheng Wan3, Christine A. Biron1, Marco E. Bianchi4, Haichao Wang5, and Wen-Ming Chu1 1 Department of Molecular Microbiology and Immunology, Brown University, Providence, RI; 2 San Raffaele Scientific Institute, Milano, Italy; 3 Department of Biology, Providence College, Providence, RI; 4 San Raffaele University, Faculty of Medicine, Milano, Italy; 5 Department of Emergency Medicine, North Shore-Long Island Jewish Research Institute, Manhasset, NY CpG-DNA or its synthetic analog CpG-ODN activates innate immunity through Toll-like receptor 9 (TLR9). However, the mechanism of TLR9 activation by CpG-DNA remains elusive. Here we have identified HMGB1 as a CpG-ODN–binding protein. HMGB1 interacts and preassociates with TLR9 in the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), and hastens TLR9's redistribution to early endosomes in response to CpG-ODN. CpG-ODN stimulates macrophages and dendritic cells to secrete HMGB1; in turn, extracellular HMGB1 accelerates the delivery of CpG-ODNs to its receptor, leading to a TLR9-dependent augmentation of IL-6, IL-12, and TNF secretion. Loss of HMGB1 leads to a defect in the IL-6, IL-12, TNF, and iNOS response to CpG-ODN. However, lack of intracellular TLR9-associated HMGB1 can be compensated by extracellular HMGB1. Thus, the DNA-binding protein HMGB1 shuttles in and out of immune cells and regulates inflammatory responses to CpG-DNA. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Tang, R. Kang, W. Xiao, H. Zhang, M. T. Lotze, H. Wang, and X. 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