Modulation of tissue factor expression by rapamycin and FK-506 in lipopolysaccharide-stimulated human mononuclear cells and serum-stimulated aortic smooth muscle cells.

Inflammation is a key pathogenic component of atherosclerosis;rnit also promotes thrombosis, a process underlying acute coronaryrnevents and stroke. Cells present in atherosclerotic plaquernshow abnormal tissue factor (TF) expression. Macrolides, inrnaddition to their antimicrobial properties,have antiinflammatoryrneffects that might help prevent atherothrombosis.The aim of thisrnstudy was to determine the effect of an immunosuppressantrnmacrolide,rapamycin (Sirolimus),on the expression ofTF and itsrninhibitor (TFPI) by monocytic cells (human blood mononuclearrnandTHP-1 cells) and human aortic smooth muscle cells, in comparisonrnwith FK-506 and azithromycin. In monocytic cells, rapamycinrnand FK-506 inhibited LPS-induced TF activity, antigen rnrnand mRNA expression through a transcriptional mechanism involvingrnNF-κ B. In smooth muscle cells, rapamycin and azithromycinrnhad no effect on serum-induced TF expression, whilernFK-506 increased serum-induced TF protein and mRNA expression.rnTFPI levels in the culture supernatants of serum-stimulatedrnsmooth muscle cells were not modified by any of the threernmacrolides. Rapamycin slightly inhibits TFPI induction by LPS inrnmonocytic cells. In addition to its recently established efficacy inrnthe prevention of stent restenosis, the inhibitory effect ofrnrapamycin on theTF pathway might have interesting therapeuticrnimplications.