DISRUPTION OF ENDOTHELIAL MICROFILAMENTS SELECTIVELY REDUCES THE TRANSENDOTHELIAL MIGRATION OF MONOCYTES

The transendothelial migration of leukocytes (diapedesis) is a central event in inflammatory and immunological processes. Although leukocyte -endothelium interactions occurring during diapedesis have been invest igated intensively little is known about the actual transmigration and the molecular mechanisms involved. Toward this end we analyzed whethe r the endothelial cytoskeleton plays a direct role during the transend othelial migration of monocytes. Filter-grown monolayers of human micr ovascular endothelial cells (HMEC-1) were treated with cytoskeleton st abilizing or destabilizing drugs and the effect of this treatment on t he transmigration of peripheral blood monocytes was analyzed in a two- chamber assay. Our results show that taxol-induced stabilization of mi crotubules causes a reduction of leukocyte transmigration through HMEC -1, while the opposite effect is induced by the destabilization of mic rotubules with colchicine or nocodazol. Disruption of microfilaments w ith cytochalasin B or latrunculin A, on the other hand, significantly reduces the transendothelial migration although monocyte adhesion and endothelial permeability for macromolecules are slightly increased. An active participation of the endothelial microfilament system with a d irect role of unconventional, calmodulin-regulated myosins is suggeste d by the finding that monocyte transmigration is decreased upon treatm ent of the endothelial cells with the Ca2+/CaM antagonist triflouperaz ine. (C) 1998 Academic Press.