Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:365-374
© 1997 American Heart Association, Inc.
Articles |
Regulation of the Tissue Factor Gene in Human Monocytic Cells
Role of AP-1, NF-
B/Rel, and Sp1 Proteins in Uninduced and Lipopolysaccharide-Induced Expression
Departments of Immunology and Vascular Biology, 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. E-mail nmackman@scripps.edu.
Tissue factor (TF) expression by peripheral blood monocytes during sepsis initiates intravascular thrombosis. Bacterial lipopolysaccharide (LPS) rapidly induces TF gene transcription in monocytes. The human TF promoter contains binding sites for the transcription factors AP-1, c-Rel/p65, Egr-1, and Sp1. NF-B/Rel proteins have been shown to physically interact with both AP-1 and Sp1 proteins. In this study, we investigated the role of these transcription factors in uninduced and LPS-induced TF gene expression in human monocytic THP-1 cells. Deletional analysis indicated that five Sp1 sites mediated basal expression in uninduced cells. The two AP-1 sites bound c-Fos/c-Jun heterodimers in both unstimulated and LPS-stimulated cells. Maximal LPS induction of the TF promoter required the two AP-1 sites and the B site within the LPS response element. Disruption of the conserved spacing between the proximal AP-1 site and the B site abolished LPS induction. Replacement of the two AP-1 sites with intrinsically bent DNA partially restored LPS induction, suggesting an additional structural role for the AP-1 sites. Synergistic transactivation of the LPS response element in Drosophila Schneider cells by coexpression of c-Fos, c-Jun, c-Rel, and p65 or c-Jun and p65 required the transactivation domains of c-Jun and p65. These data indicated that c-Fos/c-Jun, c-Rel/p65, and Sp1 regulate TF gene expression in human monocytic cells.
Key Words: thrombosis • tissue factor • gene regulation • transcription factors
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