The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism
Kazuhiro Abeyama, … , Noboru Taniguchi, Ikuro Maruyama
Kazuhiro Abeyama, … , Noboru Taniguchi, Ikuro Maruyama
Published May 2, 2005
Citation Information: J Clin Invest. 2005;115(5):1267-1274. https://doi.org/10.1172/JCI22782.
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Article Hematology

The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism

Abstract

Thrombomodulin (TM) is an endothelial anticoagulant cofactor that promotes thrombin-mediated formation of activated protein C (APC). We have found that the N-terminal lectin-like domain (D1) of TM has unique antiinflammatory properties. TM, via D1, binds high-mobility group-B1 DNA-binding protein (HMGB1), a factor closely associated with necrotic cell damage following its release from the nucleus, thereby preventing in vitro leukocyte activation, in vivo UV irradiation–induced cutaneous inflammation, and in vivo lipopolysaccharide-induced lethality. Our data also demonstrate antiinflammatory properties of a peptide spanning D1 of TM and suggest its therapeutic potential. These findings highlight a novel mechanism, i.e., sequestration of mediators, through which an endothelial cofactor, TM, suppresses inflammation quite distinctly from its anticoagulant cofactor activity, thereby preventing the interaction of these mediators with cell surface receptors on effector cells in the vasculature.

Authors

Kazuhiro Abeyama, David M. Stern, Yuji Ito, Ko-ichi Kawahara, Yasushi Yoshimoto, Motoyuki Tanaka, Tomonori Uchimura, Nobuo Ida, Yoshiaki Yamazaki, Shingo Yamada, Yasuhiko Yamamoto, Hiroshi Yamamoto, Satoshi Iino, Noboru Taniguchi, Ikuro Maruyama

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RAGE-dependent and -independent mechanism of HMGB1-mediated events and t...
RAGE-dependent and -independent mechanism of HMGB1-mediated events and the inhibitory effects of TM and TM-derived peptides. (A and B) Skin inflammation was induced in the mouse ear using UV irradiation. C57/BL6 mice (RAGE+/+; white bars) received rhs-TM alone, sRAGE alone, or TM-derived peptides (each at 100 nmol/kg; i.p.) combined with sRAGE (25 nmol/kg; i.p.) at 1 hour and 12 hours after exposure to UV irradiation (n = 8 per group). RAGE-null mice (C57BL/6 strain; black bars) were UV irradiated and were treated with sRAGE (25 nmol/kg), rhs-TM, or TM-derived peptides (each at 100 nmol/kg; i.p.). After 3 days, ear swelling (A) and infiltrating leukocytes (B) were assessed. *P < 0.05 and **P < 0.01, compared with UV-irradiated, PBS-treated controls. #P < 0.05 and ##P < 0.01, compared with UV-irradiated RAGE-null mice. (C and D) Mice (wild-type C57BL/6 and RAGE-null on the C57BL/6 background) received LPS (10 mg/kg; i.p.) alone or in the presence of TM, P-D1, P-D2+3, and PBS. (C) Effect of rhs-TM or TM-derived peptides on LPS-induced lethality. Mice received 3 i.p. doses (100 nmol/kg/mouse) of anti-HMGB1 or control IgY at 2, 12, and 24 hours after LPS challenge. (D) Mice were treated with LPS and also received either anti-HMGB1 IgY or nonimmune IgY (3 i.p. doses of 2 mg/kg/mouse of IgY at 2, 12, and 24 hours after LPS). In C and D, (–/–) indicates that RAGE-null mice were used, and (+/+) indicates that strain-matched controls were used.