Effects of tacrolimus hydrate (FK-506) on the expression of tissue factor in THP-1 human monocyte cell line.

Abstract

Accelerated coronary atherosclerosis in cardiac allografts is a major factor limiting survival after heart transplantation, and activation of the coagulation system contributes to accelerated transplant atherosclerosis. Accordingly, increased tissue factor (TF) expression by monocyte/macrophages may play a pivotal role underlying deposition of fibrin in the affected vessels. To evaluate the potential effects of an important immunosuppressive agent, tacrolimus hydrate (FK-506), on monocyte/macrophages and their response to lipopolysaccharide (LPS), we exposed human monocyte/macrophage cell line (THP-1 cells), to LPS and characterized its procoagulant activity (PCA). FK-506 exerted a concentration-dependent inhibitory effect on LPS (10 micrograms/ml) induction of procoagulant activity, identified as TF activity as judged from immunostaining of TF antigen and by functional characterization with the use of coagulation factor VII-deficient plasma and an antibody against human TF. In addition, the reverse transcription polymerase chain reaction demonstrated reduced expression of TF mRNA in LPS-stimulated THP-1 cells exposed to FK-506. Thus, FK-506 acts favorably not only as a direct immunomodulating agent but also as an alleviator of local activation of the coagulation cascade contributing to transplant arteriopathy through modulation of monocyte expression of TF.