Inhibitory control of TGF-β1 on the activation of Rap1, CD11b, and transendothelial migration of leukocytes

beta 2-Integrins are a family of dimeric adhesion molecules expressed on leukocytes. Their capacity to bind ligand is regulated by their state of activation. CD11b, an alpha M beta 2 integrin, is implicated in a number of physiological and pathological events such as inflammation, thrombosis, or atherosclerosis. The GTPase Rap1 is essential for its activation and could therefore play a strategic role in the regulation of leukocyte functioning. Because low levels of circulating TGF-beta have been linked with severe atherosclerosis, we have assessed the role of this cytokine in the regulation of Rap1 and CD11b activation in differentiated U937 cells and in human peripheral blood monocytes. TGF-beta 1 caused a significant reduction in the expression of CD11b but not in the expression of other integrins tested. More importantly, TGF-beta 1 greatly reduced the capacity of PMA or chemokines to activate CD11b and Rap 1, a phenomenon paralleled by a loss of the Epac transcript and a reduction in 8-pCPT-2'-O-Me-cAMP-mediated activation of Rap1. This inhibition diminished the capacity of monocytes to migrate across a monolayer of endothelial cells. The inhibitory effect of TGF-beta 1 on Rap1 activity may exert a general protective influence against aberrant transendothelial migration, thereby holding inflammatory responses in check.