title: 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.affiliation: Department of Microbiology, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Ju Ho
authors.initials: JH
authors.lastname: Youn
authors.forename: Man Sup
authors.initials: MS
authors.lastname: Kwak
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Kim
authors.forename: Yeounjung
authors.initials: Y
authors.lastname: Ji
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Min
authors.forename: Ji-Ho
authors.initials: JH
authors.lastname: Yoo
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Choi
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Cho
authors.forename: Jeon-Soo
authors.initials: JS
authors.lastname: Shin
mesh_terms: D000209:Acute-Phase Proteins / Q000037:antagonists & inhibitors; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002460:Cell Line; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000097:blood / Q000276:immunology*; D024243:HMGB1 Protein / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000008:administration & dosage / Q000138:chemical synthesis / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; D000099231:Lipopolysaccharide-Binding Protein