SELECTIVE SUPPRESSION OF ENDOTHELIAL-CELL ACTIVATION BY ARACHIDONIC-ACID

Endothelial cell (EC) activation plays a key role in inflammation, thr ombosis and organ rejection. Normally, EC are in a quiescent state in which their function is to prevent coagulation and thrombosis, and to participate in the regulation of leukocyte migration from the bloodstr eam into the tissue. Upon activation with cytokines or other stimuli, EC up-regulate a number of genes, including E-selectin (ELAM-1), inter cellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule ( VCAM)-1, interleukin (IL)-1, IL-8, tissue factor (TF), plasminogen act ivator inhibitor-1 (PAI-1), MCP-1 (monocyte chemoattractant protein-1) and endothelial cell inducible gene (ECI-6). Arachidonic acid (AA) is produced by several cell types, including EC, and acts on various cel ls. We report here that AA inhibits the up-regulation of some, but not all genes that are induced with EC activation in a dose-dependent man ner. AA suppresses TNF-alpha, IL-1 alpha, LPS or PMA-induced E-selecti n expression, as well as mRNA accumulation of E-selectin, ICAM-1 and I L-8 stimulated by TNF-alpha. The inhibition appears to be at the level of transcription. At the same time under the same conditions AA does not, repress mRNA accumulation for PAI-1, ECI-6, MCP-1 and VCAM-1. We suggest that the induced expression of AA with EC activation may resul t in a negative feedback loop regulating further activation.