Signal transduction pathways involved in cytokine stimulation of endothelin-1 release from human vascular smooth muscle cells.
Endothelin-1 (ET-1) mRNA expression and peptide production in human vascular smooth muscle cells (HVSMCs) are markedly increased by exposure to cytokines. As the transcription factor nuclear factor-kappaB (NF-kappaB) often mediates the effects of cytokines in target cells the aim of this study was to determine whether the production of ET-1 following exposure of HVSMCs to cytokines depends upon activation of NF-kappaB. BAY 11-7082, an inhibitor of cytokine-induced inhibitor protein (IkappaB) phosphorylation, inhibited cytokine-stimulated upregulation of preproendothelin-1 mRNA expression and ET-1 peptide production. In addition, immunoblotting showed that cytokine stimulation of ET-1 release in VSMCs involves nuclear translocation of NF-kappaB. In conclusion, NF-kappaB activation is involved in the stimulation by cytokines of ET-1 release from HVSMCs. As upregulated production of ET-1 within VSMCs may underlie the causative role of ET-1 in a number of disease states this finding indicates that NF-kappaB within HVSMCs could be central to a number of vascular pathologies.
Woods
M
M
Department of Cardiac, Vascular and Inflammation Research, St. Bartholomew's Hospital and the Royal London School of Medicine and Dentistry, London, UK.
Wood
E G
EG
Mitchell
J A
JA
Warner
T D
TD
D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism*; D016232:Endothelins / Q000235:genetics; D006801:Humans; D020672:I-kappa B Proteins; D007371:Interferon-gamma / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D004268:DNA-Binding Proteins; D019332:Endothelin-1; D016232:Endothelins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011498:Protein Precursors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D007371:Interferon-gamma