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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Figure 2

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TM, via D1, prevents proinflammatory effects of HMGB1 in vitro. (A) Effe...
TM, via D1, prevents proinflammatory effects of HMGB1 in vitro. (A) Effect of HMGB1 on NF-κB–dependent gene transcription. THP-1 cells were transfected with an NF-κB promoter-reporter (SEAP) construct. Then, THP-1 cells (106 cells/ml) were incubated for 16 hours at 37°C with the indicated concentration of HMGB1, and reporter expression was determined. Recombinant sRAGE (10 nM) or rhs-TM (TM; 100 nM) was added as indicated. (B) Human peripheral blood mononuclear phagocytes (106 cells/ml) were loaded with DCF-DA and were incubated for 1 hour at 37°C in medium alone (N) or with HMGB1 (10 nM) in medium. As indicated, rhs-TM, P-D1, P-D2+3, E456, or sRAGE was added (100 nM each). Then, the formation of DCF was determined. *P < 0.05 and **P < 0.01, compared with untreated controls. #P < 0.05, compared with the paired control group without sRAGE treatment.