TRANSCRIPTIONAL REGULATION OF TISSUE FACTOR EXPRESSION IN HUMAN ENDOTHELIAL-CELLS

Tissue factor (TF) expression by endothelial cells is implicated in th rombotic episodes in patients with a variety of clinical disorders. In a baboon model of lethal sepsis, TF is expressed by endothelial cells in the splenic microvasculature. In vitro, endothelial cells are indu ced to express TF in response to tumor necrosis factor-alpha (TNF-alph a), interleukin-1 beta (IL-1 beta), and bacterial endotoxin (lipopolys accharide [LPS]). Here, we identified cis-acting regulatory elements t hat control TF gene transcription in primary human endothelial cells. Functional studies showed that the TF promoter contained a 56-bp enhan cer (-227 to -172 bp), which included two activator protein-1 (AP-1) s ites and a kappa B-like site, that mediated induction by TNF-alpha, IL -1 beta, and LPS. Electrophoretic mobility shift assays demonstrated t hat endothelial cells contained constitutive AP-1 binding activity, wh ereas the kappa B-like site, 5'-CGGAGTITTCC-3', bound an inducible nuc lear complex composed of c-Rel-p65 heterodimers. Taken together, our d ata suggest that induction of TF gene transcription in endothelial cel ls is mediated by functional interactions between Fos-Jun and c-Rel-p6 5 heterodimers.