INHIBITION OF TISSUE FACTOR GENE ACTIVATION IN CULTURED ENDOTHELIAL-CELLS BY CURCUMIN - SUPPRESSION OF ACTIVATION OF TRANSCRIPTION FACTORS EGR-1, AP-1, AND NF-KAPPA-B

Binding of plasma factor VII(a) to tissue factor (TF) initiates the co agulation cascade. In health, TF is not expressed in endothelial cells . However, endothelial cells express TF in response to lipopolysacchar ide (LPS), tumor necrosis factor-alpha (TNF alpha), and other biologic al stimuli. TF expression by endothelial cells is implicated in thromb otic disorders in patients with a variety of clinical disorders. in th e present study, we demonstrate that curcumin (diferulolylmethane), a known anticarcinogenic and anti-inflammatory agent, inhibited phorbol 12-myristate 13-acetate (PMA), LPS, TNF alpha, and thrombin-induced TF activity and TF gene transcription in human endothelial cells. The pr esent data show that curcumin prevented the activation of c-Rel/p65, w hich is essential for TF gene activation in endothelial cells, by impa iring the proteolytic degradation inhibitor protein, I kappa B alpha. The data also show that curcumin downregulated AP-1 binding activity. The present studies are the first to demonstrate that PMA, but not LPS , TNF alpha and thrombin, induced Egr-1 binding to the second serum-re sponsive region (SRR-2) of TF promoter and that curcumin inhibited the PMA-induced Egr-1 binding to SRR-2. Overall, the data suggest that th e anticarcinogenic and anti-inflammatory properties of curcumin may be : related to its ability to inhibit cellular gene expression regulated by transcription factors NF-kappa B, AP-1, and Egr-1.