This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 28/10/1825    most recent ATVBAHA.107.150631v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ito, T. Articles by Maruyama, I. Search for Related Content PubMed PubMed Citation Articles by Ito, T. Articles by Maruyama, I.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1825.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

Proteolytic Cleavage of High Mobility Group Box 1 Protein by Thrombin-Thrombomodulin Complexes

Takashi Ito; Ko-ichi Kawahara; Kohji Okamoto; Shingo Yamada; Minetsugu Yasuda; Hitoshi Imaizumi; Yuko Nawa; Xiaojie Meng; Binita Shrestha; Teruto Hashiguchi; Ikuro Maruyama

From the Laboratory and Vascular Medicine (T.I., KI.K., Y.N., X.M., B.S., T.H., I.M.), Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima; Department of Surgery 1 (K.O.), School of Medicine, University of Occupational and Environmental Health, Kitakyushu; Shino-Test Corporation (S.Y.), Sagamihara; First Department of Surgery (M.Y.), Hamamatsu University School of Medicine, Hamamatsu; Department of Traumatology and Critical Care Medicine (H.I., Y.N.), Sapporo Medical University School of Medicine, Sapporo, Japan.

Correspondence to Ikuro Maruyama, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan. E-mail rinken{at}m3.kufm.kagoshima-u.ac.jp

Objective— High mobility group box 1 protein (HMGB1) was identified as a mediator of endotoxin lethality. We previously reported that thrombomodulin (TM), an endothelial thrombin-binding protein, bound to HMGB1, thereby protecting mice from lethal endotoxemia. However, the fate of HMGB1 bound to TM remains to be elucidated.

Methods and Results— TM enhanced thrombin-mediated cleavage of HMGB1. N-terminal amino acid sequence analysis of the HMGB1 degradation product demonstrated that thrombin cleaved HMGB1 at the Arg10-Gly11 bond. Concomitant with the cleavage of the N-terminal domain of HMGB1, proinflammatory activity of HMGB1 was significantly decreased (P<0.01). HMGB1 degradation products were detected in the serum of endotoxemic mice and in the plasma of septic patients with disseminated intravascular coagulation (DIC), indicating that HMGB1 could be degraded under conditions in which proteases were activated in the systemic circulation.

Conclusions— TM not only binds to HMGB1 but also aids the proteolytic cleavage of HMGB1 by thrombin. These findings highlight the novel antiinflammatory role of TM, in which thrombin-TM complexes degrade HMGB1 to a less proinflammatory form.

Thrombomodulin (TM), an endothelial thrombin-binding protein, can bind and sequester high mobility group box 1 (HMGB1). In the present study, we examined the end results of this binding, and found that thrombin-TM complexes degrade HMGB1 to a less proinflammatory form.

Key Words: high mobility group box 1 • sepsis • disseminated intravascular coagulation • thrombin • thrombomodulin

This article has been cited by other articles:

				Y. Nawa, K.-i. Kawahara, S. Tancharoen, X. Meng, H. Sameshima, T. Ito, Y. Masuda, H. Imaizumi, T. Hashiguchi, and I. Maruyama Nucleophosmin may act as an alarmin: implications for severe sepsis J. Leukoc. Biol., September 1, 2009; 86(3): 645 - 653. [Abstract] [Full Text] [PDF]