Inhibition of ADAM10 and 8 reduces transendothelial migration of the monocytic cell line THP1 in vitro (P5066)

Abstract Metalloproteases of the A Disintegrin And Metalproteases (ADAM) family are important molecular mediators of inflammation. ADAMs participate at all stages of inflammation via the proteolytic cleavage of cell surface molecules. It has been shown that leukocyte expressed ADAM8 and ADAM17 are important during the initial rolling of leukocytes on the endothelium. However, the role of leukocyte expressed ADAMs in transendothelial migration and chemotaxis remains to be investigated and in particular it is still unclear to what extent ADAM10 and ADAM9 contribute to leukocyte migration. In this study we show that treatment of leukocytes with a pharmaceutical ADAM10 inhibitor reduced both the in vitro transendothelial migration and the chemotaxis of the monocytic cell line THP1. The combined pharmaceutical inhibition of both ADAM10 and ADAM17 did not further suppress leukocyte migration in either experimental setting. The subsequent analysis of THP1 cells with a gene silencing of ADAM8, 9, 10 or 17 in transendothelial migration and chemotaxis experiments revealed that ADAM8 and ADAM10 are critically involved in THP1 cell migration. While ADAM9 did not seem to be required ADAM17 was only of minor importance for the migration of THP1 cells. This study analyses the role of the four proteases ADAM8, 9, 10 and 17 in the migration of leukocytic cells. It shows that ADAM8 and ADAM10 are crucial for the in vitro transendothelial migration and chemotaxis of the monocytic cell line THP1.