Activated platelets induce tissue factor expression on human umbilical vein endothelial cells by ligation of CD40.
CD40 is a type I member of the tumour necrosis factor (TNF) receptor superfamily of proteins, and is present on a wide variety of cells including vascular endothelial cells. Ligation of this receptor on endothelial cells is known to increase expression of inflammatory adhesion molecules. We have recently demonstrated that platelets express the ligand of CD40 (CD154) within seconds of exposure to agonist, and interact with endothelial cells to participate directly in the induction of an inflammatory response. Here we show that activated platelets induce tissue factor (TF) expression on endothelial cells in a CD40/CD154-dependent manner, and that the magnitude of this response can equal that induced by TNFe. Moreover, CD40 ligation on endothelial cells downregulates the expression of thrombomodulin. We also show that CD40-mediated TF expression is less sensitive to inhibition with the oxidative radical scavenger pyrrolidine dithiocarbamate than is that mediated by TNFalpha, indicating that CD40 has a distinct signalling pathway. Tissue factor is a cell membrane protein which functions as the main trigger of the extrinsic pathway of blood coagulation, and its expression on endothelial cells is implicated in wound healing and angiogenesis. Since platelets are among the first cells involved in haemostasis following tissue injury, our data showing that ligation of CD40 by CD154 induces a procoagulant phenotype on vascular endothelial cells suggests that platelets may play an important role in the induction of wound healing.
Slupsky
J R
JR
Haemostasis Research Unit, Max-Planck-Institute for Physiological and Clinical Research, Kerckhoff-Klinik GmbH, Bad Nauheim, Germany. jr.slupsky@mail.uni-wuerzburg.de
Kalbas
M
M
Willuweit
A
A
Henn
V
V
Kroczek
R A
RA
Müller-Berghaus
G
G
D001792:Blood Platelets / Q000378:metabolism; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D016166:Free Radical Scavengers; D005786:Gene Expression Regulation; D006487:Hemostasis / Q000502:physiology; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000502:physiology*; D010641:Phenotype; D015539:Platelet Activation; D011759:Pyrrolidines / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D018180:Thrombomodulin / Q000096:biosynthesis / Q000235:genetics; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins; D014945:Wound Healing / Q000502:physiology
D019013:CD40 Antigens; D016166:Free Radical Scavengers; D008024:Ligands; D008562:Membrane Glycoproteins; D011759:Pyrrolidines; D013859:Thiocarbamates; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; C020972:pyrrolidine dithiocarbamic acid; D013925:Thromboplastin