MAP-kinase dependent induction of monocytic procoagulant activity by β2-integrins

beta(2)-Integrin adhesion molecules play crucial roles in monocyte transmigration and adherence to the inflamed extracellular matrix. While integrin engagement contributes to inflammatory cell activation, little is known about the precise signaling pathways that are important to integrin-dependent monocyte activation. We examined the role of tyrosine phosphorylation and extracellular-signal regulated kinase (ERK) activity in beta(2)-integrin signaling in monocytes. Crosslinking of the LFA-1 (CD11a/CD18) and MAC-1 (CD11b/CD18) integrins on the surface of THP-1 monocytic cells induced the accumulation of tyrosine phosphoproteins. As part of this signal both ERK-1 and ERK-2 are tyrosine phosphorylated. In vitro kinase assays documented an increase in ERK-2 activity following both LFA-1 and MAC-1 cross-linking. beta(2)-Integrin crosslinking also led to a marked increase in 4-h procoagulant activity (PCA) in THP-1 cells and purified human monocytes. Inhibition of tyrosine phosphorylation by genistein (10 mu g/ml), or selective ERK inhibition with PD98059 (10 mu M), was able to block the integrin-dependent induction of PCA in both THP-1 cells and human monocytes, Thus, beta(2) integrin signaling in monocytic cells can how through the tyrosine phosphorylation and activation of the ERR mitogen activated protein kinases, which is essential for the subsequent expression of tissue factor, These results suggest that the ERK proteins likely function to integrate various adhesion-dependent signals during the process of monocyte transmigration. (C) 1998 Academic Press.