Bacterial Endotoxin Induces the Release of High Mobility Group Box 1 via the IFN-β Signaling Pathway
Bacterial Endotoxin Induces the Release of High Mobility Group Box 1 via the IFN-β Signaling Pathway
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DOI：
10.4049/jimmunol.0801364
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发表时间：
2009-02-15
影响因子：
4.4
通讯作者：
Oh, Kwon Ik
中科院分区：
文献类型：
--
作者：
Kim, Ju-Hyun;Kim, Seon-Ju;Oh, Kwon Ik
脓毒症是一种破坏性的疾病，其特征是全身炎症反应。最近，高迁移率族蛋白 1 (HMGB1) 被确定为脓毒症引起的致死性全身炎症的必要且充分的介质。然而，尽管 HMGB1 具有临床重要性，但其释放机制仍不清楚。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 Toll/IL,-1R 结构域包含接头诱导的 IFN-β 接头。此外，我们还发现 NO 作为 IFN-β 信号传导的下游分子。此外，JAK 抑制剂治疗以及 STAT-1 或 IFN-β 受体缺陷减少了内毒素血症小鼠模型中 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有益于脓毒症的治疗。免疫学杂志，2009，182：2458-2466。
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. The Journal of Immunology, 2009, 182: 2458-2466.