title: Synergistic induction of endothelin-1 by tumor necrosis factor alpha and interferon gamma is due to enhanced NF-kappaB binding and histone acetylation at specific kappaB sites.
abstract: Endothelin-1 (ET-1) is a potent vasoconstrictor and co-mitogen for vascular smooth muscle and is implicated in pulmonary vascular remodeling and the development of pulmonary arterial hypertension. Vascular smooth muscle is an important source of ET-1. Here we demonstrate synergistic induction of preproET-1 message RNA and release of mature peptide by a combination of tumor necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma) in primary human pulmonary artery smooth muscle cells. This induction was prevented by pretreatment with the histone acetyltransferase inhibitor anacardic acid. TNFalpha induced a rapid and prolonged pattern of nuclear factor (NF)-kappaB p65 subunit activation and binding to the native preproET-1 promoter. In contrast, IFNgamma induced a delayed activation of interferon regulatory factor-1 without any effect on NF-kappaB p65 nuclear localization or consensus DNA binding. However, we found cooperative p65 binding and histone H4 acetylation at distinct kappaB sites in the preproET-1 promoter after stimulation with both TNFalpha and IFNgamma. This was associated with enhanced recruitment of RNA polymerase II to the ATG start site and read-through of the ET-1 coding region. Understanding such mechanisms is crucial in determining the key control points in ET-1 release. This has particular relevance to developing novel treatments targeted at the inflammatory component of pulmonary vascular remodeling.
authors: Department of Critical Care, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom. s.wort@imperial.ac.uk
authors: Stephen J
authors: SJ
authors: Wort
authors: Misako
authors: M
authors: Ito
authors: Pai-Chien
authors: PC
authors: Chou
authors: Shaun K
authors: SK
authors: Mc Master
authors: Rekha
authors: R
authors: Badiger
authors: Elen
authors: E
authors: Jazrawi
authors: Patricia
authors: P
authors: de Souza
authors: Timothy W
authors: TW
authors: Evans
authors: Jane A
authors: JA
authors: Mitchell
authors: Liao
authors: L
authors: Pinhu
authors: Kaz
authors: K
authors: Ito
authors: Ian M
authors: IM
authors: Adcock
mesh_terms: D000107:Acetylation / Q000187:drug effects; D048729:Anacardic Acids / Q000494:pharmacology; D002478:Cells, Cultured; D018387:Codon, Initiator / Q000378:metabolism; D019332:Endothelin-1 / Q000096:biosynthesis*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D020218:Response Elements / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D048729:Anacardic Acids; D018387:Codon, Initiator; D019332:Endothelin-1; D006657:Histones; C498143:RELA protein, human; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C088115:anacardic acid; D007371:Interferon-gamma; D051548:Histone Acetyltransferases; D012319:RNA Polymerase II