ENDOTHELIN-1 STIMULATES THE BIOSYNTHESIS OF TUMOUR NECROSIS FACTOR IN MACROPHAGES : ET-RECEPTORS, SIGNAL TRANSDUCTION AND INHIBITION BY DEXAMETHASONE

摘要: Endothelin-1 (ET-1) enhances the biosynthesis of interleukin-6 (IL-6) in endothelial cells and bone marrow-derived stromal rat. This study investigates (i) whether ET-1 stimulates formation tumour necrosis factor alpha (TNF alpha) or interferon-gamma (IFN gamma) cultured macrophages anaesthetized Incubation J774.2 with (0.001-1 microM) caused a concentration- time-dependent increase concentration TNF alpha, but not IFN gamma, culture medium. The by stimulation was abolished pretreatment protein synthesis inhibitor cycloheximide, (ii) selective ETA-receptor antagonists BQ-123 BQ-485 (but ETB-receptor antagonist BQ-788), (iii) tyrosine kinase inhibitors genistein tyrphostin AG126, (iv) glucocorticoid, dexamethasone. inhibition dexamethasone activated is due to lipocortin-1 (LC1), as it reduced monoclonal antibody against LC1. Systemic administration (i.v.) (1 nmol.kg-1) rats rapid sustained (maximum: 45 min; return baseline: within 180 min) rise plasma levels alpha. first demonstration that can release proinflammatory cytokines vitro vivo. generation involves (in sequence) activation ETA-receptors, resulting phosphorylation intracellular proteins, of, hitherto, unknown transcription factors, finally translation gene. points pro-inflammatory role diseases associated local (e.g. atherosclerosis, heart failure) systemic inflammation (circulatory shock), which are high levels.