Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:612-621
© 1995 American Heart Association, Inc.
Articles |
Transcriptional Regulation of Tissue Factor Expression in Human Endothelial Cells
From the Department of Immunology, The Scripps Research Institute, La Jolla, Calif.
Correspondence to Nigel Mackman, PhD, The Scripps Research Institute, 10666 N Torrey Pines Rd, IMM-17, La Jolla, CA 92037.
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–
(TNF-), interleukin-1ß (IL-1ß), 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 
B-like site, that mediated induction by TNF-,
IL-1ß, and LPS. Electrophoretic mobility shift assays demonstrated
that endothelial cells contained constitutive AP-1 binding activity,
whereas the B-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.
Key Words: endothelium • tissue factor • gene expression
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