Synergistic Induction of Endothelin-1 by Tumor Necrosis Factor α and Interferon γ Is due to Enhanced NF-κB Binding and Histone Acetylation at Specific κB Sites

摘要: Endothelin-1 (ET-1) is a potent vasoconstrictor and co-mitogen for vascular smooth muscle implicated in pulmonary remodeling the development of arterial hypertension. Vascular an important source ET-1. Here we demonstrate synergistic induction preproET-1 message RNA release mature peptide by combination tumor necrosis factor α (TNFα) interferon γ (IFNγ) primary human artery cells. This was prevented pretreatment with histone acetyltransferase inhibitor anacardic acid. TNFα induced rapid prolonged pattern nuclear (NF)-κB p65 subunit activation binding to native promoter. In contrast, IFNγ delayed regulatory factor-1 without any effect on NF-κB localization or consensus DNA binding. However, found cooperative H4 acetylation at distinct κB sites promoter after stimulation both IFNγ. associated enhanced recruitment polymerase II ATG start site read-through ET-1 coding region. Understanding such mechanisms crucial determining key control points release. has particular relevance developing novel treatments targeted inflammatory component remodeling.