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

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 
Citation
 EUROPEAN JOURNAL OF IMMUNOLOGY, Vol.41(9) : 2753-2762, 2011 
Journal Title
 EUROPEAN JOURNAL OF IMMUNOLOGY 
ISSN
 0014-2980 
Issue Date
2011
MeSH
Acute-Phase Proteins/antagonists & inhibitors ; Animals ; Binding Sites/drug effects ; Carrier Proteins/antagonists & inhibitors ; Cell Line ; Disease Models, Animal ; Endotoxemia/blood ; Endotoxemia/immunology* ; HMGB1 Protein/chemistry ; HMGB1 Protein/immunology ; HMGB1 Protein/metabolism* ; Humans ; Leukocytes, Mononuclear/drug effects ; Leukocytes, Mononuclear/immunology ; Leukocytes, Mononuclear/metabolism* ; Leukocytes, Mononuclear/pathology ; Lipopolysaccharides/immunology ; Lipopolysaccharides/metabolism* ; Membrane Glycoproteins/antagonists & inhibitors ; Mice ; Mice, Inbred BALB C ; Peptide Fragments/administration & dosage ; Peptide Fragments/chemical synthesis ; Peptide Fragments/metabolism* ; Protein Binding/drug effects ; Tumor Necrosis Factor-alpha/blood
Keywords
Endotoxin shock ; High mobility group box 1 ; Inflammation ; Lipopoly saccharide
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
Files in This Item:
T201102691.pdf Download
DOI
10.1002/eji.201141391
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Kwak, Man Sup(곽만섭) ORCID logo https://orcid.org/0000-0002-3989-3016
Shin, Jeon Soo(신전수) ORCID logo https://orcid.org/0000-0002-8294-3234
Youn, Ju Ho(윤주호)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/93615
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