title: High mobility group box 1 protein binding to lipopolysaccharide facilitates transfer of lipopolysaccharide to CD14 and enhances lipopolysaccharide-mediated TNF-alpha production in human monocytes.
abstract: 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-alpha 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.
authors: Department of Microbiology, Brain Korea 21 Project for Medical Science, National Core Research Center for Nanomedical Technology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Ju Ho
authors: JH
authors: Youn
authors: Young Joo
authors: YJ
authors: Oh
authors: Eun Sook
authors: ES
authors: Kim
authors: Ji Eun
authors: JE
authors: Choi
authors: Jeon-Soo
authors: JS
authors: Shin
mesh_terms: D000818:Animals; D016466:CHO Cells; D002384:Catalysis; D006224:Cricetinae; D003412:Cricetulus; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008823:Micelles; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism*; D011485:Protein Binding; D012995:Solubility; D020349:Surface Plasmon Resonance; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D024243:HMGB1 Protein; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008823:Micelles; D014409:Tumor Necrosis Factor-alpha