The p55 tumor necrosis factor receptor (CD120a) induces endothelin-1 synthesis in endothelial and epithelial cells

Synthesis of the vasoconstrictor peptide endothelin-1 by endothelial and ep ithelial cells is strongly induced by tumor necrosis factor alpha (TNF-alph a). The actions of TNF-alpha are mediated by two transmembrane receptors of approximately 55 (p55, CD120a) and 75 kDa (p75, CD120b). Reagents activati ng selectively these receptor subtypes have been used to identify which TNF receptor mediates the induction of endothelin-1 synthesis. Stimulation of bovine aortic endothelial cells or human HEp-2 epithelial cells with a p55- selective mutant of human TNF-alpha (R32W-S86T) induced significant and con centration-dependent increases in endothelin-1 release. A p75 receptor-sele ctive TNF-alpha mutant(D143N-A145R) was ineffective alone or in combination with the p55-selective mutant. Competitive binding experiments with [I-125 ]TNF-alpha showed the p55-selective mutant, but not the p75-selective mutan t, to inhibit the binding of [I-125]TNF-alpha to endothelial and HEp-2 cell s. Similar results were obtained with the p55 agonist antibody htrl in both cell lines. These results establish the p55 TNF receptor as the main recep tor involved in the induction of endothelin-1 synthesis by TNF-alpha. (C) 2 000 Elsevier Science B.V. Ail rights reserved.