title: Cardiac glycosides are potent inhibitors of interferon-β gene expression.
abstract: Here we report that bufalin and other cardiac glycoside inhibitors of the sodium-potassium ATPase (sodium pump) potently inhibit the induction of the interferon-β (IFNβ) gene by virus, double-stranded RNA or double-stranded DNA. Cardiac glycosides increase the intracellular sodium concentration, which appears to inhibit the ATPase activity of the RNA sensor RIG-I, an essential and early component in the IFNβ activation pathway. This, in turn, prevents the activation of the critical transcription factors IRF3 and NFκB. Bufalin inhibition can be overcome by expressing a drug-resistant variant of the sodium pump and knocking down the pump by short hairpin RNA inhibits IFNβ expression. Thus, bufalin acts exclusively through the sodium pump. We also show that bufalin inhibits tumor necrosis factor (TNF) signaling, at least in part by interfering with the nuclear translocation of NFκB. These findings suggest that bufalin could be used to treat inflammatory and autoimmune diseases in which IFN or TNF are hyperactivated.
authors.affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Junqiang
authors.initials: J
authors.lastname: Ye
authors.forename: Shuibing
authors.initials: S
authors.lastname: Chen
authors.forename: Tom
authors.initials: T
authors.lastname: Maniatis
mesh_terms: D002018:Bufanolides / Q000737:chemistry / Q000494:pharmacology; D002301:Cardiac Glycosides / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000196:embryology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000037:antagonists & inhibitors / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002018:Bufanolides; D002301:Cardiac Glycosides; D004791:Enzyme Inhibitors; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D020365:RNA Helicases; D000254:Sodium-Potassium-Exchanging ATPase; C022777:bufalin