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

Kazuhiro Abeyama, David 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

Research output: Contribution to journalArticle

362 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1267-1274
Number of pages8
JournalJournal of Clinical Investigation
Volume115
Issue number5
DOIs
StatePublished - Jan 1 2005

Fingerprint

High Mobility Group Proteins
Thrombomodulin
Anti-Inflammatory Agents
Anticoagulants
HMGB1 Protein
Inflammation
Cell Surface Receptors
Protein C
Lectins
Thrombin
Lipopolysaccharides
Leukocytes
Skin

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. / Abeyama, Kazuhiro; Stern, David; Ito, Yuji; Kawahara, Ko Ichi; Yoshimoto, Yasushi; Tanaka, Motoyuki; Uchimura, Tomonori; Ida, Nobuo; Yamazaki, Yoshiaki; Yamada, Shingo; Yamamoto, Yasuhiko; Yamamoto, Hiroshi; Iino, Satoshi; Taniguchi, Noboru; Maruyama, Ikuro.

In: Journal of Clinical Investigation, Vol. 115, No. 5, 01.01.2005, p. 1267-1274.

Research output: Contribution to journalArticle

Abeyama, K, Stern, D, Ito, Y, Kawahara, KI, Yoshimoto, Y, Tanaka, M, Uchimura, T, Ida, N, Yamazaki, Y, Yamada, S, Yamamoto, Y, Yamamoto, H, Iino, S, Taniguchi, N & Maruyama, I 2005, 'The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism', Journal of Clinical Investigation, vol. 115, no. 5, pp. 1267-1274. https://doi.org/10.1172/JCI22782
Abeyama, Kazuhiro ; Stern, David ; Ito, Yuji ; Kawahara, Ko Ichi ; Yoshimoto, Yasushi ; Tanaka, Motoyuki ; Uchimura, Tomonori ; Ida, Nobuo ; Yamazaki, Yoshiaki ; Yamada, Shingo ; Yamamoto, Yasuhiko ; Yamamoto, Hiroshi ; Iino, Satoshi ; Taniguchi, Noboru ; Maruyama, Ikuro. / The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. In: Journal of Clinical Investigation. 2005 ; Vol. 115, No. 5. pp. 1267-1274.
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