title: Endogenous HMGB1 is required in endotoxin tolerance.
abstract: BACKGROUND
  High-mobility group box 1 protein (HMGB1), a downstream inflammatory response modifier in sepsis and endotoxemia, alters endotoxin tolerance by affecting cellular hyporesponsiveness and tumor necrosis factor α and interleukin 1 production.
  
  
  OBJECTIVE
  Endogenous HMGB1 signaling mechanisms during low-dose lipopolysaccharide (LPS)-induced endotoxin tolerance were investigated.
  
  
  METHODS
  BALB/c mice were preconditioned with either 0.1 mL low-dose LPS (0.2 mg/kg) or phosphate-buffered saline (PBS) (control) followed by treatment with three consecutive injections of anti-HMGB1, IgY (an nonspecific antibody), or PBS, at 2, 12, and 22 h, respectively, Mice were then subjected to 0.1 mL high-dose LPS (10 mg/kg) or PBS at 24 h. Serum and hepatic tissue samples were obtained 1 or 3 h after final treatments. Signaling mechanisms were further investigated in the serum and hepatic tissues of mice preconditioned with 0.1 mL HMGB1 (1 mg/kg), low-dose LPS (0.2 mg/kg), or PBS for 1 h, and then high-dose LPS treatment for 3 h.
  
  
  RESULTS
  The signaling mechanisms involved in low-dose LPS preconditioning required enhanced endogenous HMGB1 expression and secretion. Neutralizing endogenous HMGB1 with anti-HMGB1 antibodies following low-dose LPS preconditioning altered endotoxin tolerance by increasing serum tumor necrosis factor α, reducing hepatic interleukin-1R-associated kinase M expression, and partially restoring nuclear factor κB in vivo. The translocation from nucleus to cytoplasm of endogenous HMGB1 in RAW264.7 cells was also observed during low-dose LPS-induced endotoxin tolerance.
  
  
  CONCLUSIONS
  Increased interleukin-1R-associated kinase M and decreased nuclear factor κB activity in endotoxin tolerance is associated with endogenous HMGB1 expression after low-dose LPS preconditioning. These findings provide a basis for a better mechanistic understanding and the development of safer clinical therapeutics utilizing induced endotoxin tolerance.
authors.affiliation: Department of Burns, the 3rd Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Li
authors.forename: Chengqun
authors.initials: C
authors.lastname: Luo
authors.forename: Chaoqi
authors.initials: C
authors.lastname: Yin
authors.forename: Chen
authors.initials: C
authors.lastname: Peng
authors.forename: Rong
authors.initials: R
authors.lastname: Han
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.forename: Quangyong
authors.initials: Q
authors.lastname: He
authors.forename: Jianda
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D002460:Cell Line; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D024243:HMGB1 Protein / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D007108:Immune Tolerance / Q000276:immunology*; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018805:Sepsis / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D018836:Inflammation Mediators; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse
keywords: HMGB1 protein; IRAK-M; Immune tolerance; Inflammation; Lipopolysaccharide; Nuclear factor κB