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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 1, 2006 Accepted May 28, 2007 A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA Stanimir Ivanov, Ana-Maria Dragoi, Xin Wang, Corrado Dallacosta, Jennifer Louten, Giovanna Musco, Giovanni Sitia, George S. Yap, Yinsheng Wan, Christine A Biron, Marco E Bianchi, Haichao Wang, and Wen-Ming Chu* Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, United States San Raffaele Scientific Institute, Milano, Italy Department of Biology, Providence College, Providence, RI, United States Faculty of Medicine, San Raffaele University, Milano, Italy Department of Emergency Medicine, North Shore-Long Island Jewish Research Institute, Manhasset, NY, United States * Corresponding author; email: wen-ming_chu{at}brown.edu. CpG-DNA or its synthetic analogue 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 pre-associates with TLR9 in the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), and hastens its 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 IL-6, IL-12, TNF, and iNOS response to CpG-ODN. However, the 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. 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