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(Circulation Research. 2009;104:943.)
© 2009 American Heart Association, Inc.

Molecular Medicine

TRAIL/Apo2L Mediates the Release of Procoagulant Endothelial Microparticles Induced by Thrombin In Vitro

A Potential Mechanism Linking Inflammation and Coagulation

Stéphanie Simoncini^*, Makon-Sébastien Njock^*, Stéphane Robert, Laurence Camoin-Jau, José Sampol, Jean-Robert Harlé, Catherine Nguyen, Françoise Dignat-George, Francine Anfosso

From the Institut National de la Santé et de la Recherche Médicale UMR608 (S.S., M.-S.N., S.R., L.C.-J., J.S., F.D.-G., F.A.), Physiopathologie de l'Endothelium, Universite Mediterranee, Faculte de Pharmacie Marseille, France; Hopital de la Conception (L.C.-J., J.-R.H., F.D.-G.), Assistance Publique-Hopitaux de Marseille, France; and Institut National de la Santé et de la Recherche Médicale U928 (C.N.), Technologies Avancées pour le Génome et la Clinique, Marseille, France.

Correspondence to Dr F. Anfosso, INSERM UMR608, Physiopathologie de l'Endothélium, Faculté de Pharmacie, 27 Bd Jean Moulin 13385 Marseille cedex 05, France. E-mail francine.anfosso{at}pharmacie.univ-mrs.fr

Microparticles are small vesicles playing a crucial role in cell communication by promoting prothrombotic and proinflammatory responses. However, the molecular mechanisms underlying their release are still elusive. We previously established that thrombin promoted the generation of endothelial microparticles (EMPs). In the present study, gene profiling identified TRAIL/Apo2L, a cytokine belonging to the tumor necrosis factor- superfamily, as a target of thrombin. Thrombin increased the expression of cell-associated and soluble forms of TRAIL (sTRAIL) in HMEC-1 cells and human umbilical vein endothelial cells (HUVECs). Blocking TRAIL by specific antibodies or by small interfering RNA reduced both the number and the procoagulant activity of EMPs released by thrombin. Consistent with an involvement of sTRAIL in thrombin-induced EMP release, we showed that (1) exogenously added sTRAIL generated procoagulant EMPs; (2) supernatants from thrombin-stimulated endothelial cells induced EMP release by HMEC-1 cells and HUVECs, whereas those recovered from TRAIL knockdown endothelial cells displayed no effect. TRAIL/TRAIL-R2 complex mediated EMP release by initiating the recruitment of adaptor proteins and the activation of nuclear factor B. Moreover, sTRAIL modulated intercellular adhesion molecule-1 and interleukin-8 expression induced by thrombin by a downstream pathway involving nuclear factor B activation. Our data reveal a novel mechanism controlling EMP release and identify TRAIL as a key partner in the pathway linking coagulation and inflammation elicited by thrombin.

Key Words: endothelium • vesiculation • cell signaling • inflammation • coagulation • thrombosis

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