Effects of prostacyclin analogues on human endothelial cell tissue factor expression.
Prostacyclin analogues have been reported to inhibit the expression of tissue factor procoagulant activity in human monocytes, primarily by elevating intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP). The present studies have investigated whether prostacyclins can also inhibit tissue factor expression in endothelial cells. Iloprost, carbacyclin, and ciprostene had no effect on human umbilical vein endothelial tissue factor activity induced by lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha), or interleukin-1 beta (IL-1 beta). Iloprost failed to elevate intracellular levels of cAMP, even when combined with a phosphodiesterase inhibitor. In contrast, forskolin increased endothelial cAMP and inhibited tissue factor expression. Conditioned medium from LPS-challenged monocytic THP-1 cells, which contained both TNF-alpha and IL-1 beta, induced endothelial cell procoagulant activity to levels 20-fold higher than those achieved in response to LPS alone. Iloprost abolished LPS-induced TNF-alpha secretion by THP-1 cells and inhibited IL-1 beta secretion by 45%. In keeping with this, iloprost reduced levels of TNF-alpha and IL-1 beta mRNA in LPS-challenged cells. Treatment of THP-1 cells with iloprost strongly inhibited the ability of conditioned medium to induce endothelial tissue factor expression, an effect that was mimicked by treating the medium with blocking antibodies to the cytokines. We conclude that although prostacyclin analogues do not directly suppress endothelial tissue factor expression due to their failure to elevate cAMP, they may do so indirectly by inhibiting the amplification produced by monocyte-derived cytokines.
Crutchley
D J
DJ
Miami Heart Research Institute, Miami Beach, Fla 33140.
Conanan
L B
LB
Toledo
A W
AW
Solomon
D E
DE
Que
B G
BG
D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000737:chemistry; D000242:Cyclic AMP / Q000032:analysis; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology*; D011464:Epoprostenol / Q000494:pharmacology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000187:drug effects / Q000235:genetics; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D007375:Interleukin-1 / Q000032:analysis; D009000:Monocytes / Q000378:metabolism; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D017077:Culture Media, Conditioned; D016207:Cytokines; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D013925:Thromboplastin; D011464:Epoprostenol; D000242:Cyclic AMP; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D016285:Iloprost