Endothelin-1 induces production of the neutrophil chemotactic factor interleukin-8 by human brain-derived endothelial cells.
Increased levels of endothelin-1 (Et-1), a potent vasoconstrictor, have been correlated with hypertension and neuronal damage in ischemic/reperfusion injury. The presence of polymorphonuclear cells (PMNs) in the brain has been shown to be directly responsible for this observed pathology. To address the question of whether Et-1 plays a role in this process, human brain-derived endothelial cells (CNS-ECs) were cultured with Et-1. The results demonstrate that Et-1 induces production of the neutrophil chemoattractant interleukin-8 (IL-8) twofold to threefold after 72 hours; mRNA was maximal after 1 hour of stimulation. Conditioned culture medium derived from Et-1-stimulated CNS-ECs induced a chemotactic response in the PMN migration assay. The inflammatory cytokines tumor necrosis factor-alpha (TNF) and IL-1beta functioned additively 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-1 on IL-8 production. However, Et-1 did not modulate intercellular adhesion molecule-1 (ICAM-1) expression. These data demonstrate that Et-1 may be a risk factor in ischemic/reperfusion injury by inducing increased levels of the neutrophil chemoattractant IL-8.
Hofman
F M
FM
Departments of Pathology, Medicine, and Neurology, University of Southern California, Los Angeles; and the Departments of Biology and Neuroscience, University of California, Riverside, CA, USA.
Chen
P
P
Jeyaseelan
R
R
Incardona
F
F
Fisher
M
M
Zidovetzki
R
R
D002545:Brain Ischemia / Q000453:epidemiology / Q000378:metabolism; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000166:cytology*; D002550:Cerebral Veins / Q000166:cytology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004357:Drug Synergism; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D007375:Interleukin-1 / Q000494:pharmacology; D016753:Interleukin-10 / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D020033:Protein Isoforms / Q000502:physiology; D015427:Reperfusion Injury / Q000453:epidemiology / Q000378:metabolism; D012307:Risk Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D017077:Culture Media, Conditioned; D019332:Endothelin-1; D007375:Interleukin-1; D016209:Interleukin-8; D020033:Protein Isoforms; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10