Regulation of tissue factor gene expression in monocytes and endothelial cells: Thromboxane A2 as a new player

Abstract

Tissue factor (TF) is the primary activator of the coagulation cascade. Under normal conditions, endothelial cells (ECs) and blood cells, such as monocytes, do not express TF. However, bacterial lipopolysaccharide (LPS) induces TF expression in monocytes and this leads to disseminated intravascular coagulation during endotoxemia and sepsis. A variety of stimuli induce TF expression in ECs in vitro, although it is unclear how much TF is expressed by the endothelium in vivo. LPS induction of TF gene expression in monocytic cells and ECs is mediated by various intracellular signaling pathways and the transcription factors NF-ĸB, AP-1 and Egr-1. In contrast, vascular endothelial cell growth factor (VEGF) induces TF gene expression in ECs via the transcription factors NFAT and Egr-1. Similarly, oxidized phospholipids (such as 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine) induce TF expression in ECs and possibly monocytes via NFAT and Egr-1. Thromboxane A2 (TXA2) can now be added to the list of stimuli that induce TF gene expression in both monocytes and ECs. Interestingly, inhibition of the TX-prostanoid (TP) receptor also reduces TF expression in with tumor necrosis factor (TNF)-α stimulated ECs and LPS stimulated monocytes, which suggests that TP receptor antagonist may be useful in reducing pathologic TF expression in the vasculature and blood.