Chelerythrine, a selective protein kinase C inhibitor, counteracts pyrogen-induced expression of tissue factor without effect on thrombomodulin down-regulation in endothelial cells.
Endotoxin, interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) dose-dependently increased the expression of tissue factor and at the same time induced thrombomodulin down-regulation on the surface of cultured bovine aortic endothelial cells. Chelerythrine, a selective protein kinase C inhibitor, strongly reduced endotoxin-, IL1 beta- and TNF alpha-induced tissue factor expression but remained without effect with regard to thrombomodulin down-regulation measured in parallel. On the contrary, staurosporine, a highly potent, non-selective PKC inhibitor, simultaneously abolished tissue factor expression and thrombomodulin down-regulation induced by endotoxin, IL1 beta and TNF alpha. These results show that protein kinase C is deeply involved in the process leading to pyrogen-induced tissue factor expression and suggest that thrombomodulin down-regulation is regulated by a different pathway.
Herbert
J M
JM
Sanofi Recherche, Toulouse, France.
Savi
P
P
Laplace
M C
MC
Dumas
A
A
Dol
F
F
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D053119:Benzophenanthridines; D002417:Cattle; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004731:Endotoxins / Q000037:antagonists & inhibitors; D007375:Interleukin-1 / Q000037:antagonists & inhibitors; D010617:Phenanthridines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011749:Pyrogens / Q000037:antagonists & inhibitors*; D019311:Staurosporine; D018180:Thrombomodulin / Q000096:biosynthesis* / Q000235:genetics; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D000470:Alkaloids; D053119:Benzophenanthridines; D004731:Endotoxins; D007375:Interleukin-1; D010617:Phenanthridines; D011749:Pyrogens; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; C044101:endotoxin, Escherichia coli; D013925:Thromboplastin; C016299:chelerythrine; D011493:Protein Kinase C; D019311:Staurosporine