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 endothelin stimulation on cytokine production, we explored the effect of endothelin-1 (ET-1) on interleukin-6 (IL-6) gene expression. ET-1 augmented the production of IL-6 in human umbilical vein endothelial cells (HUVEC) by 2- to 5-fold and synergized with IL-1 to induce a 150-fold increase in IL-6 secretion, compared with spontaneous production. The peak 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 concentration of 100 pM, in the presence of 1 ng/ml of IL-1. ET-1-induced IL-6 mRNA expression was significant within 4 h of stimulation and persisted for 18 h. Similarly, the ETB receptor-specific agonist, IRL-1620, also augmented IL-6 mRNA expression and IL-6 protein production in HUVEC. Our results suggest that endothelin may play a role at the vascular inflammatory site by modulating cytokine production through ETB receptor activation in endothelial cells of human origin.