Transcriptional regulation of the endothelin-1 gene by TNF-alpha.
Cytokines, such as tumor necrosis factor-alpha (TNF-alpha), induce profound alterations in endothelial cell phenotype and are implicated in the organ dysfunction that characterizes septic shock. We explored whether TNF-alpha modulates cellular expression of endothelin-1 (ET-1). ET-1 is a potent vasoconstrictor peptide released by endothelial, vascular smooth muscle, and mesangial cells that could function as a paracrine/autocrine regulator of vascular tone and proliferation. We found that TNF-alpha induced release of ET-1 from bovine aortic endothelial cells (BAEC) in a time- and concentration-dependent manner. Rates of ET-1 release were maximal over 1-8 h and declined to, or below, baseline values after 16 h. When measured at 8 h, TNF-alpha augmented ET-1 release over the range 0.1-250 ng/ml (threshold, 0.1 ng/ml; 50% effective dose, 1.6 +/- 1.2 ng/ml; maximal effect, 100 ng/ml). The increase in secretion was accompanied by a corresponding increase in the transcriptional rate of the ET-1 gene resulting in augmented preproendothelin-1 mRNA transcript levels. TNF-alpha-stimulated increases in ET-1 gene transcription were not dependent on new protein synthesis. Actinomycin D chase experiments suggested that enhanced stability of preproendothelin-1 mRNA could not account for the increase in ET-1 transcript levels. TNF-alpha increased ET-1 release and preproendothelin-1 mRNA content in bovine renal artery and bovine glomerular capillary endothelial cells, demonstrating that the TNF-alpha effect was evident in endothelial cells derived from a variety of sources. Furthermore, augmented ET-1 expression in response to TNF-alpha was evident in bovine glomerular mesangial cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Marsden
P A
PA
Department of Medicine, St. Michael's Hospital, University of Toronto, Ontario, Canada.
Brenner
B M
BM
D000818:Animals; D002478:Cells, Cultured; D019332:Endothelin-1; D016232:Endothelins / Q000235:genetics* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005796:Genes; D007678:Kidney Glomerulus / Q000166:cytology / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha