Kim Ju-Hyun, Kim Seon-Ju, Lee Im-Soon, Lee Myung-Shik, Uematsu Satoshi, Akira Shizuo, Oh Kwon Ik
Department of Pathology, Hallym University College of Medicine, Chuncheon, Korea.
J Immunol. 2009 Feb 15;182(4):2458-66. doi: 10.4049/jimmunol.0801364.
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.
脓毒症是一种以全身炎症反应为特征的毁灭性病症。最近，高迁移率族蛋白B1（HMGB1）被确定为脓毒症所致致死性全身炎症的必要且充分的介质。然而，尽管其具有临床重要性，HMGB1释放的机制仍不清楚。在本研究中，我们证明IFN-β介导的JAK/STAT途径对于LPS或大肠杆菌诱导的HMGB1释放至关重要，这依赖于含Toll/IL-1R结构域的接头诱导IFN-β接头分子。此外，我们表明NO作为IFN-β信号传导的下游分子。此外，在内毒素血症小鼠模型中，JAK抑制剂治疗以及STAT-1或IFN-β受体缺陷减少了HMGB1的释放。我们的结果表明，脓毒症中HMGB1的释放依赖于IFN-β信号轴；因此，选择性抑制IFN-β信号传导的治疗药物可能对脓毒症的治疗有益。
