Monocytic thrombomodulin promotes cell adhesion through interacting with its ligand, Lewisy.
The leukocyte adhesion cascade involves multiple events that efficiently localize circulating leukocytes into the injured sites to mediate inflammatory responses. From rolling to firm adhesion, the interactions between adhesion molecules have pivotal roles in increasing the avidity of leukocytes to endothelial cells. Thrombomodulin (TM), an essential anticoagulant protein in the vasculature, is also expressed on leukocytes. We previously demonstrated that Lewisy(Ley), a specific ligand of TM, is upregulated in inflamed endothelium and is involved in leukocyte adhesion. The current study aimed to investigate whether leukocyte-expressed TM promotes cell adhesion by interacting with Ley. Using human monocytic THP-1 cells as an in vitro cell model, we showed that TM increases THP-1 cell adhesion to inflamed endothelium as well as to Ley-immobilized surface. When THP-1 adhered to activated endothelium and Ley-immobilized surface, the TM distribution became polarized. Addition of soluble Leyto a suspension of THP-1 cells with TM expression triggered an increase in the level of phosphorylated p38 mitogen-activated protein kinase (MAPK), which enabled THP-1 to adhere firmly to intercellular adhesion molecule (ICAM)-1 by activating β2integrins. In vivo, macrophage infiltration and neointima formation following arterial ligation-induced vascular injury were higher in wild-type TM (TMflox/flox) than in myeloid-specific TM-deficient (LysMcre/TMflox/flox) mice. Taken together, these results suggest a novel function for TM as an adhesion molecule in monocytes, where it enhances cell adhesion by binding Ley, leading to β2integrin activation via p38 MAPK.
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Wei-Ling
WL
Lin
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Chia-Chi
CC
Chen
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Guey-Yueh
GY
Shi
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Chih-Yuan
CY
Ma
Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Chuan-Fa
CF
Chang
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Hua-Lin
HL
Wu
D000818:Animals; D018821:CD18 Antigens / Q000378:metabolism; D002448:Cell Adhesion; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007983:Lewis Blood Group Antigens / Q000378:metabolism; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology*; D058426:Neointima / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D000074084:THP-1 Cells; D018180:Thrombomodulin / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018821:CD18 Antigens; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; D008024:Ligands; D034741:RNA, Small Interfering; D018180:Thrombomodulin; D018799:Intercellular Adhesion Molecule-1; D048051:p38 Mitogen-Activated Protein Kinases