Regulation of tissue factor in microvascular dermal endothelial cells

Area of Science:

• Vascular Biology
• Inflammation Research
• Coagulation Cascade

Background:

• Inflammation activates the coagulation cascade, leading to thrombosis.
• Endothelial cells normally prevent clotting but can become thrombogenic upon inflammatory mediator exposure.
• Tissue factor expression on endothelial cells is a critical step in initiating blood coagulation.

Purpose of the Study:

• To investigate the mechanisms regulating tissue factor expression in human dermal microvasculature.
• To identify the specific signaling pathways involved in tumor necrosis factor-alpha-induced tissue factor expression.

Main Methods:

• Human dermal microvascular endothelial cells were treated with tumor necrosis factor-alpha.
• The effects of inhibitors targeting nuclear factor-kappaB (MG-132), MEK1 (PD98059), and p38 mitogen-activated protein kinase (SB203580) were assessed.
• Tissue factor protein and mRNA levels, as well as heterogeneous nuclear RNA, were measured.

Main Results:

• Tumor necrosis factor-alpha induced time- and concentration-dependent tissue factor expression.
• p38 mitogen-activated protein kinase inhibition (SB203580) significantly blocked tissue factor induction.
• Nuclear factor-kappaB inhibition (MG-132) partially blocked induction, while MEK1 inhibition (PD98059) had minimal effect.
• Both SB203580 and MG132 reduced tissue factor mRNA and gene transcription.

Conclusions:

• Tumor necrosis factor-alpha induces tissue factor expression transcriptionally in dermal microvascular endothelial cells.
• p38 mitogen-activated protein kinase plays a major role in this transcriptional regulation.
• Nuclear factor-kappaB also contributes transcriptionally, whereas MEK1 is not significantly involved.