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Bacterial Endotoxin Induces the Release of High Mobility Group Box 1 via the IFN-β Signaling Pathway¹

Ju-Hyun Kim^*,, Seon-Ju Kim^*,, Im-Soon Lee, Myung-Shik Lee, Satoshi Uematsu^¶, Shizuo Akira^¶ and Kwon Ik Oh^2,*,

^* Department of Pathology and Infectious Disease Medical Research Center, Hallym University College of Medicine, Chuncheon, Korea; Department of Biological Sciences, College of Sciences, Konkuk University, Seoul, Korea; Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; and ^¶ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Korea Science and Engineering Foundation grant funded by the Korea government (Ministry of Science and Technology) (R13-2005-022-01004-0).

² Address correspondence and reprint requests to Dr. Kwon Ik Oh, Department of Pathology, Hallym University College of Medicine, 39 Hallymdaehak-gil, Chucheon, Gangwon-Do 200-702, Korea. E-mail address: kwonik{at}hallym.ac.kr

³ Abbreviations used in this paper: HMGB1, high mobility group box 1; CaMK, calcium/calmodulin-dependent protein kinase; poly(I:C), polyinosinic-polycytidylic acid; TRIF, Toll/IL-1R domain-containing adaptor-inducing IFN-β.