HMGB1 enhances the proinflammatory activity of lipopolysaccharide by promoting the phosphorylation of MAPK p38 through receptor for advanced glycation end products.
High mobility group box-1 (HMGB1) protein was originally characterized as a nuclear DNA-binding protein, and was described to have an extracellular role when involved in cellular activation and proinflammatory responses. In the present study, we have found that the proinflammatory activity of recombinant HMGB1 proteins is determined by the containing endotoxin level, and HMGB1 that contains few endotoxins fails to stimulate macrophages to secrete proinflammatory cytokines. HMGB1 acts as a ligand of receptor for advanced glycation end products (RAGE) and works in synergy with LPS in activating the macrophages in vitro. In vivo, intra-articular injections of HMGB1 act in synergy with LPS to induce experimental arthritis in mice. HMGB1 promotes the phosphorylation of MAPK p38 and the activation of NF-kappaB through RAGE, and then enhances the expression of proinflammatory cytokines. These results demonstrate that HMGB1 enhances the proinflammatory activity of LPS by promoting the phosphorylation of MAPK p38 and by the activation of NF-kappaB through RAGE.
Qin
Yang-Hua
YH
Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, Shanghai, Peoples Republic of China.
Dai
Sheng-Ming
SM
Tang
Gu-Sheng
GS
Zhang
Jun
J
Ren
Ding
D
Wang
Zhi-Wei
ZW
Shen
Qian
Q
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000276:immunology / Q000378:metabolism; D024243:HMGB1 Protein / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D011725:Pyridines / Q000494:pharmacology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism
D000873:Anthracenes; D016207:Cytokines; D004791:Enzyme Inhibitors; D005419:Flavonoids; D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D007093:Imidazoles; D008070:Lipopolysaccharides; D011725:Pyridines; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C432165:pyrazolanthrone; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one