Identification of lipopolysaccharide-binding peptide regions within HMGB1 and their effects on subclinical endotoxemia in a mouse model.

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.

• Authors: Ju Ho Youn, Man Sup Kwak, Jie Wu, Eun Sook Kim, Yeounjung Ji, Hyun Jin Min, Ji-Ho Yoo, Ji Eun Choi, Hyun-Soo Cho, Jeon-Soo Shin
• Journal: European journal of immunology (Eur J Immunol) Vol. 41 Issue 9 Pg. 2753-62 (Sep 2011) ISSN: 1521-4141 [Electronic] Germany
• PMID: 21660935 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Acute-Phase Proteins
• Carrier Proteins
• HMGB1 Protein
• Lipopolysaccharides
• Membrane Glycoproteins
• Peptide Fragments
• Tumor Necrosis Factor-alpha
• lipopolysaccharide-binding protein

Topics

• Acute-Phase Proteins (antagonists & inhibitors)
• Animals
• Binding Sites (drug effects)
• Carrier Proteins (antagonists & inhibitors)
• Cell Line
• Disease Models, Animal
• Endotoxemia (blood, immunology)
• HMGB1 Protein (chemistry, immunology, metabolism)
• Humans
• Leukocytes, Mononuclear (drug effects, immunology, metabolism, pathology)
• Lipopolysaccharides (immunology, metabolism)
• Membrane Glycoproteins (antagonists & inhibitors)
• Mice
• Mice, Inbred BALB C
• Peptide Fragments (administration & dosage, chemical synthesis, metabolism)
• Protein Binding (drug effects)
• Tumor Necrosis Factor-alpha (blood)