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-β-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-β adaptor. Additionally, we show that NO acts as a downstream molecule of the IFN-β signaling. Furthermore, the JAK inhibitor treatment as well as the STAT-1 or IFN-β receptor deficiency reduced HMGB1 release in a murine model of endotoxemia. Our results suggest that HMGB1 release in sepsis is dependent on the IFN-β signaling axis; thus, therapeutic agents that selectively inhibit IFN-β signaling could be beneficial in the treatment of sepsis.