期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 473, 期 4, 页码 1005-1012出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2016.04.007
关键词
Integrin; Thrombomodulin; Inflammation; Adhesion molecules
资金
- JSPS KAKENHI [24590579, 25461125, 26861520]
- Asahi Kasei Pharma Corporation
- Grants-in-Aid for Scientific Research [25461125, 25460396, 24590579, 16K08581, 16K09513, 16K20386, 16K15759, 26861520] Funding Source: KAKEN
LFA-1 (alpha L beta 2) and Mac-1 (alpha M beta 2) 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 alpha L integrin-blocking mAb, alpha M integrin-blocking mAb, and beta 2 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 (alpha L beta 2) and Mac-1 (alpha M beta 2) 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. (C) 2016 Elsevier Inc. All rights reserved.
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