TRAIL/Apo2L mediates the release of procoagulant endothelial microparticles induced by thrombin in vitro: a potential mechanism linking inflammation and coagulation.
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-alpha 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 kappaB. Moreover, sTRAIL modulated intercellular adhesion molecule-1 and interleukin-8 expression induced by thrombin by a downstream pathway involving nuclear factor kappaB 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.
Simoncini
Stéphanie
S
Faculte de Pharmacie, Institut National de la Santé et de la Recherche Médicale UMR608, Physiopathologie de l'Endothelium, Universite Mediterranee, Marseille, France.
Njock
Makon-Sébastien
MS
Robert
Stéphane
S
Camoin-Jau
Laurence
L
Sampol
José
J
Harlé
Jean-Robert
JR
Nguyen
Catherine
C
Dignat-George
Françoise
F
Anfosso
Francine
F
D001777:Blood Coagulation; D055252:Cell-Derived Microparticles / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism*; D013927:Thrombosis / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
C508606:CXCL8 protein, human; D017077:Culture Media, Conditioned; D016209:Interleukin-8; C498143:RELA protein, human; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D051996:Transcription Factor RelA; D018799:Intercellular Adhesion Molecule-1; D013917:Thrombin