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

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

Research output: Contribution to journalArticle

44 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2753-2762
Number of pages10
JournalEuropean Journal of Immunology
Volume41
Issue number9
DOIs
Publication statusPublished - 2011 Sep 1

Fingerprint

Endotoxemia
Lipopolysaccharides
Peptides
HMG-Box Domains
Blood Cells
CD14 Antigens
Lipid A
Serum
Polysaccharides

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Youn, Ju Ho ; Kwak, Man Sup ; Wu, Jie ; Kim, Eun Sook ; Ji, Yeounjung ; Min, Hyun Jin ; Yoo, Ji Ho ; Choi, Ji Eun ; Cho, Hyun Soo ; Shin, Jeon Soo. / Identification of lipopolysaccharide-binding peptide regions within HMGB1 and their effects on subclinical endotoxemia in a mouse model. In: European Journal of Immunology. 2011 ; Vol. 41, No. 9. pp. 2753-2762.
@article{6010b243e06f40ada0c1c932c3e71eb9,
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.",
author = "Youn, {Ju Ho} and Kwak, {Man Sup} and Jie Wu and Kim, {Eun Sook} and Yeounjung Ji and Min, {Hyun Jin} and Yoo, {Ji Ho} and Choi, {Ji Eun} and Cho, {Hyun Soo} and Shin, {Jeon Soo}",
year = "2011",
month = "9",
day = "1",
doi = "10.1002/eji.201141391",
language = "English",
volume = "41",
pages = "2753--2762",
journal = "European Journal of Immunology",
issn = "0014-2980",
publisher = "Wiley-VCH Verlag",
number = "9",

}

Identification of lipopolysaccharide-binding peptide regions within HMGB1 and their effects on subclinical endotoxemia in a mouse model. / Youn, Ju Ho; Kwak, Man Sup; Wu, Jie; Kim, Eun Sook; Ji, Yeounjung; Min, Hyun Jin; Yoo, Ji Ho; Choi, Ji Eun; Cho, Hyun Soo; Shin, Jeon Soo.

In: European Journal of Immunology, Vol. 41, No. 9, 01.09.2011, p. 2753-2762.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of lipopolysaccharide-binding peptide regions within HMGB1 and their effects on subclinical endotoxemia in a mouse model

AU - Youn, Ju Ho

AU - Kwak, Man Sup

AU - Wu, Jie

AU - Kim, Eun Sook

AU - Ji, Yeounjung

AU - Min, Hyun Jin

AU - Yoo, Ji Ho

AU - Choi, Ji Eun

AU - Cho, Hyun Soo

AU - Shin, Jeon Soo

PY - 2011/9/1

Y1 - 2011/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=80052156387&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052156387&partnerID=8YFLogxK

U2 - 10.1002/eji.201141391

DO - 10.1002/eji.201141391

M3 - Article

C2 - 21660935

AN - SCOPUS:80052156387

VL - 41

SP - 2753

EP - 2762

JO - European Journal of Immunology

JF - European Journal of Immunology

SN - 0014-2980

IS - 9

ER -