Abstract
Lipopolysaccharide (LPS) triggers deleterious systemic inflammatory responses when released into the circulation. LPS-binding protein (LBP) in the serum plays an important role in modifying LPS toxicity by facilitating its interaction with LPS signaling receptors, which are expressed on the surface of LPS-responsive cells. We have previously demonstrated that high mobility group box 1 (HMGB1) can bind to and transfer LPS, consequently increasing LPS-induced TNF-α production in human peripheral blood mononuclear cells (PBMCs). We report here on the identification of two LPS-binding domains within HMGB1. Furthermore, using 12 synthetic HMGB1 peptides, we define the LPS-binding regions within each domain. Among them, synthetic peptides HPep1 and HPep6, which are located in the A and B box domains of HMGB1, bind to the polysaccharide and lipid A moieties of LPS respectively. Both HPep1 and HPep6 peptides inhibited binding of LPS to LBP and HMGB1, LBP-mediated LPS transfer to CD14, and cellular uptake of LPS in RAW264.7 cells. These peptides also inhibited LPS-induced TNF-α release in human PBMCs and induced lower levels of TNF-α in the serum in a subclinical endotoxemia mouse model. These results indicate that HMGB1 has two LPS-binding peptide regions that can be utilized to design anti-sepsis or LPS-neutralizing therapeutics.
Highlights
Lipopolysaccharide (LPS) is the main cause of Gram-negative bacterial sepsis
We have previously demonstrated that high mobility group box 1 (HMGB1) can bind to and transfer LPS, increasing LPSinduced TNF-a production in human peripheral blood mononuclear cells (PBMCs)
We previously found that HMGB1 can bind to LPS and transfer it to CD14 thereby enhancing LPS-mediated inflammation, demonstrating that HMGB1 plays a role in LPS-mediated TNF-a production [14]
Summary
Lipopolysaccharide (LPS) is the main cause of Gram-negative bacterial sepsis. LPS consists of a lipid A component, a sugar moiety that forms the core, and an O-polysaccharide of variableÃThese authors have contributed to this study.& 2011 WILEY-VCH Verlag GmbH & Co. Lipopolysaccharide (LPS) is the main cause of Gram-negative bacterial sepsis. HMGB1 can trigger inflammation [8] and is a late mediator of endotoxemia and sepsis in both animal models and humans [9,10,11,12]. HMGB1 can form highly inflammatory complexes with CpG DNA [15, 16] and IL-1b [17], suggesting that HMGB1 is necessary but not sufficient to induce inflammation [18]. We proposed that HMGB1 can interact with LPS and transfer LPS to CD14 to enhance LPSmediated inflammation [14]; HMGB1 may transfer LPS to CD14 under the conditions where LBP is absent, such as in LBP-deficient mice [19], or where and when the level of HMGB1 is highly increased such as in Gram-negative bacterial infections [9]
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