title: Heparin inhibits the inflammatory response induced by LPS and HMGB1 by blocking the binding of HMGB1 to the surface of macrophages.
abstract: High mobility group box 1 protein (HMGB1), a nuclear non-histone DNA-binding protein, is secreted extracellularly during inflammation and is a late mediator of inflammatory responses. The pro-inflammatory activity of recombinant HMGB1 proteins is dependent upon the formation of complexes with other mediators, such as lipopolysaccharide (LPS). This study investigated the influence of heparin on LPS+HMGB1-mediated inflammatory responses in cultured macrophages and a murine sepsis model. HMGB1 promoted the phosphorylation of p38 and ERK1/2. HMGB1 enhanced the induction of the pro-inflammatory cytokine, TNF-α, by LPS in macrophages. Heparin blocked the binding of HMGB1 to the surface of macrophages, and suppressed the phosphorylation of p38 and ERK1/2, but not JNK; TNF-α secretion was also decreased. However, heparin alone did not affect LPS-induced production of TNF-α. Heparin reduced lethality in mice exposed to LPS+HMGB1. To conclude, heparin inhibited LPS-induced HMGB1-amplified inflammatory responses by blocking HMGB1 binding to macrophage surfaces. Heparin could be used therapeutically as an effective inhibitor of HMGB1-associated inflammation.
authors.affiliation: Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ling
authors.affiliation: Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yin
authors.affiliation: Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China.
authors.forename: Shan-Miao
authors.initials: SM
authors.lastname: Gou
authors.affiliation: Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China.
authors.forename: Nai-Yang
authors.initials: NY
authors.lastname: Zhan
authors.affiliation: Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China.
authors.forename: Jiong-Xin
authors.initials: JX
authors.lastname: Xiong
authors.affiliation: Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China.
authors.forename: He-Shui
authors.initials: HS
authors.lastname: Wu
authors.affiliation: Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China. Electronic address: zhiyongyang@hust.edu.cn.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Yang
authors.affiliation: Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China. Electronic address: chunyouwang52@126.com.
authors.forename: Chun-You
authors.initials: CY
authors.lastname: Wang
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004789:Enzyme Activation; D024243:HMGB1 Protein / Q000378:metabolism*; D006493:Heparin / Q000494:pharmacology*; D007249:Inflammation / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D006493:Heparin; D048052:Mitogen-Activated Protein Kinase 3
keywords: Heparin; High mobility group box 1 protein; Lipopolysaccharide; Mitogen-activated protein kinase; Tumour necrosis factor-α