学位論文 LFA-1 and Mac-1 integrins bind to the serine/threonine-rich domain of thrombomodulin

Kawamoto, Eiji

2017-03-24 , 三重大学
内容記述
LFA-1 (aLb2) and Mac-1 (aMb2) 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 anticoagulant 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 aL integrin-blocking mAb, aM integrin-blocking mAb, and b2 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 (aLb2) and Mac-1 (aMb2) 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.
本文 / Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine; Emergency and Critical Care Center, Mie University Hospital
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