title: LFA-1 and Mac-1 integrins bind to the serine/threonine-rich domain of thrombomodulin.
abstract: LFA-1 (αLβ2) and Mac-1 (αMβ2) integrins regulate leukocyte trafficking in health and disease by binding primarily to IgSF ligand ICAM-1 and ICAM-2 on endothelial cells. Here we have shown that the anti-coagulant molecule thrombomodulin (TM), found on the surface of endothelial cells, functions as a potentially new ligand for leukocyte integrins. We generated a recombinant extracellular domain of human TM and Fc fusion protein (TM-domains 123-Fc), and showed that pheripheral blood mononuclear cells (PBMCs) bind to TM-domains 123-Fc dependent upon integrin activation. We then demonstrated that αL integrin-blocking mAb, αM integrin-blocking mAb, and β2 integrin-blocking mAb inhibited the binding of PBMCs to TM-domains 123-Fc. Furthermore, we show that the serine/threonine-rich domain (domain 3) of TM is required for the interaction with the LFA-1 (αLβ2) and Mac-1 (αMβ2) integrins to occur on PBMCs. These results demonstrate that the LFA-1 and Mac-1 integrins on leukocytes bind to TM, thereby establishing the molecular and structural basis underlying LFA-1 and Mac-1 integrin interaction with TM on endothelial cells. In fact, integrin-TM interactions might be involved in the dynamic regulation of leukocyte adhesion with endothelial cells.
authors.affiliation: Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; Emergency and Critical Care Center, Mie University Hospital, 2-174 Edobashi, Tsu 514-8507, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kawamoto
authors.affiliation: Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. Electronic address: okamotot@doc.medic.mie-u.ac.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Okamoto
authors.affiliation: Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Takagi
authors.affiliation: Medical Affairs Department, Asahi Kasei Pharma Corporation, 1-105 Kanda Jinbo-cho, Chiyoda-ku, Tokyo 101-8101, Japan.
authors.forename: Goichi
authors.initials: G
authors.lastname: Honda
authors.affiliation: Faculty of Pharmaceutical Science, Suzuka University of Medical Science, 3500-3, Minamitamagaki-cho, Suzuka, Mie 513-8679, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Emergency and Critical Care Center, Mie University Hospital, 2-174 Edobashi, Tsu 514-8507, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Imai
authors.affiliation: Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. Electronic address: shimaoka@doc.medic.mie-u.ac.jp.
authors.forename: Motomu
authors.initials: M
authors.lastname: Shimaoka
mesh_terms: D018821:CD18 Antigens / Q000378:metabolism; D002448:Cell Adhesion; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D018180:Thrombomodulin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D018821:CD18 Antigens; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; C546931:THBD protein, human; D018180:Thrombomodulin
keywords: Adhesion molecules; Inflammation; Integrin; Thrombomodulin