title: 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.affiliation: Department of Laboratory and Molecular Medicine, Shin Nippon Biomedical Laboratories Inc. (SNBL), Kagoshima University, Japan. k-abeyam@m3.kufm.kagoshima-u.ac.jp
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Abeyama
authors.forename: David M
authors.initials: DM
authors.lastname: Stern
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ito
authors.forename: Ko-ichi
authors.initials: K
authors.lastname: Kawahara
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yoshimoto
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Tanaka
authors.forename: Tomonori
authors.initials: T
authors.lastname: Uchimura
authors.forename: Nobuo
authors.initials: N
authors.lastname: Ida
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamada
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iino
authors.forename: Noboru
authors.initials: N
authors.lastname: Taniguchi
authors.forename: Ikuro
authors.initials: I
authors.lastname: Maruyama
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D011486:Protein C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012867:Skin / Q000378:metabolism / Q000473:pathology; D018180:Thrombomodulin / Q000378:metabolism*; D013997:Time Factors
chemical_list: D024243:HMGB1 Protein; D011486:Protein C; D018180:Thrombomodulin