title: Interferon regulatory factor-1 mediates the release of high mobility group box-1 in endotoxemia in mice.
abstract: BACKGROUND
  The extracellular release of the danger signal high mobility group box-1 (HMGB1) has been implicated in the pathogenesis and outcomes of sepsis. Understanding the mechanisms responsible for HMGB1 release can lead to the identification of targets that may inhibit this process. The transcription factor interferon regulatory factor-1 (IRF-1) is an important mediator of innate immune responses and has been shown to participate in mortality associated with endotoxemia; however, its role in mediating the release of HMGB1 in these settings is unknown.
  
  
  METHODS
  Male IRF-1 knockout (KO) and age matched C57BL/6 wild type (WT) mice were given intraperitoneal (IP) injections of lipopolysaccharide (LPS). In some experiments, 96 hours survival rates were observed. In other experiments, mice were sacrificed 12 hours after LPS administration and sera were harvested for future analysis. In in vitro study, RAW 264.7 murine monocyte/macrophage-like cells or primary peritoneal macrophage obtained from IRF-1 KO and WT mice were cultured for LPS mediated HMGB1 release analysis. And the mechanism for HMGB1 release was analyzed by immune-precipitation.
  
  
  RESULTS
  IRF-1 KO mice experienced less mortality, and released less systemic HMGB1 compared to their WT counterparts. Exogenous administration of recombinant HMGB1 to IRF-1 KO mice returned the mortality rate to that seen originally in IRF-1 WT mice. Using cultures of peritoneal macrophages or RAW264.7 cells, in vitro LPS stimulation induced the release of HMGB1 in an IRF-1 dependent manner. And the janus associated kinase (JAK)-IRF-1 signal pathway appeared to participate in the signaling mechanisms of LPS-induced HMGB1 release by mediating acetylation of HMGB1.
  
  
  CONCLUSIONS
  IRF-1 plays a role in LPS induced release of HMGB1 and therefore may serve as a novel target in sepsis.
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China pinhuapan668@hotmail.com
authors.forename: Pin-hua
authors.initials: PH
authors.lastname: Pan
authors.forename: Jon
authors.initials: J
authors.lastname: Cardinal
authors.forename: Mo-li
authors.initials: ML
authors.lastname: Li
authors.forename: Cheng-ping
authors.initials: CP
authors.lastname: Hu
authors.forename: Allan
authors.initials: A
authors.lastname: Tsung
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism*; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D024243:HMGB1 Protein; D050856:Interferon Regulatory Factor-1; D008070:Lipopolysaccharides