Induction of Tissue Factor Production but not the Upregulation of Adhesion Molecule Expression by Ceramide in Human Vascular Endothelial Cells

Abstract

Binding of tumor necrosis factor-α (TNF-α) to p60 TNF-α receptor induces the activation of sphingomyelinase to generate ceramide, which in turn activates certain protein kinases and phosphatases, resulting in various TNF-α-mediated biological effects. We have investigated the role for the sphingomyelin/ceramide pathway in the TNF-α-induced upregulation of adhesion molecule expression and tissue factor production of human endothelial cells. TNF-α stimulated human umbilical vascular endothelial cells (HUVECs) to upregulate the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and HLA class I molecules in addition to the induction of procoagulant tissue factor production. C2-ceramide, a highly cell-permeable ceramide analog, was able to stimulate HUVECs to produce tissue factor activity as well as TNF-α. However, C2-ceramide did not stimulate HUVECs to upregulate the expression of VCAM-1, ICAM-1 and HLA class I molecules. These results suggest that there exist both the ceramide-dependent and -independent pathways in TNF-α signal transduction system in human vascular endothelial cells.