Bacterial endotoxin induces the release of high mobility group box 1 via the IFN-beta signaling pathway.
Sepsis is a devastating condition characterized by a systemic inflammatory response. Recently, high mobility group box 1 (HMGB1) was identified as a necessary and sufficient mediator of the lethal systemic inflammation caused by sepsis. However, despite its clinical importance, the mechanism of HMGB1 release has remained to be elusive. In this study, we demonstrate that the IFN-beta-mediated JAK/STAT pathway is essential for LPS or Escherichia coli-induced HMGB1 release, which is dependent on Toll/IL-1R domain-containing adapter-inducing IFN-beta adaptor. Additionally, we show that NO acts as a downstream molecule of the IFN-beta signaling. Furthermore, the JAK inhibitor treatment as well as the STAT-1 or IFN-beta receptor deficiency reduced HMGB1 release in a murine model of endotoxemia. Our results suggest that HMGB1 release in sepsis is dependent on the IFN-beta signaling axis; thus, therapeutic agents that selectively inhibit IFN-beta signaling could be beneficial in the treatment of sepsis.
Kim
Ju-Hyun
JH
Department of Pathology, Hallym University College of Medicine, Chuncheon, Korea.
Kim
Seon-Ju
SJ
Lee
Im-Soon
IS
Lee
Myung-Shik
MS
Uematsu
Satoshi
S
Akira
Shizuo
S
Oh
Kwon Ik
KI
D000818:Animals; D015153:Blotting, Western; D019446:Endotoxemia / Q000276:immunology / Q000378:metabolism; D004731:Endotoxins / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000276:immunology; D024243:HMGB1 Protein / Q000276:immunology / Q000378:metabolism*; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism*; D053612:Janus Kinases / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism
D004731:Endotoxins; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D009569:Nitric Oxide; D016899:Interferon-beta; D053612:Janus Kinases