Cardiac glycosides are potent inhibitors of interferon-beta gene expression

Here we report that bufalin and other cardiac glycoside inhibitors of the sodium-potassium ATPase (sodium pump) potently inhibit the induction of the interferon-beta (IFN beta) 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 IFN beta activation pathway. This, in turn, prevents the activation of the critical transcription factors IRF3 and NF kappa B. 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 IFN beta 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 NF kappa B. These findings suggest that bufalin could be used to treat inflammatory and autoimmune diseases in which IFN or TNF are hyperactivated.