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High Mobility Group Box 1 Protein Binding to Lipopolysaccharide Facilitates Transfer of Lipopolysaccharide to CD14 and Enhances Lipopolysaccharide-Mediated TNF- Production in Human Monocytes¹

Ju Ho Youn^*, Young Joo Oh^*, Eun Sook Kim^*, Ji Eun Choi and Jeon-Soo Shin^2,*,,

^* Department of Microbiology, Brain Korea 21 Project for Medical Science, Institute for Immunology and Immunological Diseases, and National Core Research Center for Nanomedical Technology, Yonsei University College of Medicine; and Department of Pediatrics, Seoul National University Borame Hospital, Seoul, Republic of Korea

LPS-binding protein (LBP) is a central mediator that transfers LPS to CD14 to initiate TLR4-mediated proinflammatory response. However, a possibility of another LPS transfer molecule has been suggested because LBP-deficient mice showed almost normal inflammatory response after LPS injection. In this study, we describe the novel finding that high mobility group box 1 protein (HMGB1) recently identified as a mediator of sepsis has a function of LPS transfer for a proinflammatory response. We used ELISA and surface plasmon resonance to show that HMGB1 binds LPS in a concentration-dependent manner and that the binding is stronger to lipid A moiety than to the polysaccharide moiety of LPS. This binding was inhibited by LBP and polymyxin B. Using native PAGE and fluorescence-based LPS transfer analyses, we show that HMGB1 can catalytically disaggregate and transfer LPS to both soluble CD14 protein and to human PBMCs in a dose-dependent manner. However, this effect was dramatically reduced to the baseline level when HMGB1 was heat inactivated. Furthermore, a mixture of HMGB1 and LPS treatment results in a higher increase in TNF- production in human PBMCs and peripheral blood monocytes than LPS or HMGB1 treatment alone or their summation. Thus, we propose that HMGB1 plays an important role in Gram-negative sepsis by catalyzing movement of LPS monomers from LPS aggregates to CD14 to initiate a TLR4-mediated proinflammatory response.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Korean Health 21 R&D Project (A010381 and A050260) of the Ministry of Health and Welfare, the Korea Science and Engineering Foundation through the National Core Research Center for Nanomedical Technology (R15-2004-024-00000-0), Yonsei University Research Fund (2004-0053), a faculty research grant from Yonsei University College of Medicine (2004-94), and the Brain Korea 21 Project for Medical Sciences, Republic of Korea.

² Address correspondence and reprint requests to Dr. Jeon-Soo Shin, Department of Microbiology, Yonsei University College of Medicine, 250 Seongsan-ro Seodaemoon-gu, Seoul 120-752, Republic of Korea. E-mail address: jsshin6203{at}yuhs.ac

³ Abbreviations used in this paper: LBP, LPS-binding protein; HMGB1, high mobility group box 1 protein; RAGE, receptor for advanced glycation end product; PBMo, peripheral blood monocyte; PMB, polymyxin B; SPR, surface plasmon resonance; CETP, cholesteryl ester transfer protein; PLTP, phospholipid transfer protein; BPI, bactericidal/permeability-increasing protein; DC, dendritic cell; C-HMGB1, acidic tail-deleted HMGB1; GPI, glycosylphosphatidylinositol.