ENDOTHELIN-1 INDUCES PRODUCTION OF THE NEUTROPHIL CHEMOTACTIC FACTOR INTERLEUKIN-8 BY HUMAN BRAIN-DERIVED ENDOTHELIAL-CELLS

Increased levels of endothelin-l (Et-l), a potent vasoconstrictor, hav e been correlated with hypertension and neuronal damage in ischemic/re perfusion injury. The presence of polymorphonuclear cells (PMNs) in th e brain has been shown to be directly responsible for this observed pa thology. To address the question of whether Et-l plays a role in this process, human brain-derived endothelial cells (CNS-ECs) were cultured with Et-l, The results demonstrate that Et-l induces production of th e neutrophil chemoattractant interleukin-8 (IL-8) twofold to threefold after 72 hours; mRNA was maximal after 1 hour of stimulation, Conditi oned culture medium derived from Et-l-stimulated CNS-ECs induced a che motactic response in the PMN migration assay. The inflammatory cytokin es tumor necrosis factor-alpha (TNF) and IL-1 beta functioned additive ly with Et-1 in increasing IL-8 production. In contrast, transforming growth factor-beta (TGF-beta), but not IL-10, completely abolished the effect of Et-l on IL-8 production. However, Et-l did not modulate int ercellular adhesion molecule-1 (ICAM-1) expression. These data demonst rate that Et-l may be a risk factor in ischemic/reperfusion injury by inducing increased levels of the neutrophil chemoattractant IL-8. (C) 1998 by The American Society of Hematology.