ET-1 INDUCES IL-6 GENE-EXPRESSION IN HUMAN UMBILICAL VEIN ENDOTHELIAL-CELLS - SYNERGISTIC EFFECT OF IL-1

Endothelins are a family of potent vasoactive peptides that have also been implicated in inflammation. To examine the consequence of endothe lin stimulation on cytokine production, we explored the effect of endo thelin-l (ET-1) on interleukin-6 (IL-6) gene expression. ET-1 augmente d the production of IL-6 in human umbilical vein endothelial cells (HU VEC) by 2- to Ei-fold and synergized with IL-1 to induce a 150-fold in crease in IL-6 secretion, compared with spontaneous production. The pe ak of IL-6 production was in the presence of 100 pM ET-1 after 12 h of stimulation. ET-1 augmented IL-6 mRNA expression at the optimal conce ntration of 100 pM, in the presence of 1 ng/ml of IL-1. ET-1-induced I L-6 mRNA expression was significant within 4 h of stimulation and pers isted for 18 h. Similarly, the ETB receptor-specific agonist, IRL-1620 , also augmented IL-6 mRNA expression and IL-6 protein production in H UVEC. Our results suggest that endothelin may play a role at the vascu lar inflammatory site by modulating cytokine production through ETB re ceptor activation in endothelial cells of human origin.