Transcriptional Regulation of Tissue Factor Expression in Human Endothelial Cells

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Abstract
Tissue factor (TF) expression by endothelial cells is implicated in thrombotic 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 induced to express TF in response to tumor necrosis factor–α (TNF-α), interleukin-1β (IL-1β), and bacterial endotoxin (lipopolysaccharide [LPS]). Here, we identified cis-acting regulatory elements that control TF gene transcription in primary human endothelial cells. Functional studies showed that the TF promoter contained a 56-bp enhancer (−227 to −172 bp), which included two activator protein–1 (AP-1) sites and a κB-like site, that mediated induction by TNF-α, IL-1β, and LPS. Electrophoretic mobility shift assays demonstrated that endothelial cells contained constitutive AP-1 binding activity, whereas the κB-like site, 5′-CGGAGTTTCC-3′, bound an inducible nuclear complex composed of c-Rel–p65 heterodimers. Taken together, our data suggest that induction of TF gene transcription in endothelial cells is mediated by functional interactions between Fos-Jun and c-Rel–p65 heterodimers.