title: Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from cystic fibrosis lung epithelial cells.
abstract: Cystic fibrosis (CF) is a fatal, autosomal, recessive genetic disease that is characterized by profound lung inflammation. The inflammatory process is believed to be caused by massive overproduction of the proinflammatory protein IL-8, and the high levels of IL-8 in the CF lung are therefore believed to be the central mechanism behind CF lung pathophysiology. We show here that digitoxin, at sub nM concentrations, can suppress hypersecretion of IL-8 from cultured CF lung epithelial cells. Certain other cardiac glycosides are also active but with much less potency. The specific mechanism of digitoxin action is to block phosphorylation of the inhibitor of NF-kappa B (I kappa B alpha). I kappa B alpha phosphorylation is a required step in the activation of the NF-kappa B signaling pathway and the subsequent expression of IL-8. Digitoxin also has effects on global gene expression in CF cells. Of the informative genes expressed by the CF epithelial cell line IB-3, 58 are significantly (P < 0.05) affected by gene therapy with wild-type (CFTR CF transmembrane conductance regulator). Of these 58 genes, 36 (62%) are similarly affected by digitoxin and related active analogues. We interpret this result to suggest that digitoxin can also partially mimic the genomic consequences of gene therapy with CF transmembrane conductance regulator. We therefore suggest that digitoxin, with its lengthy history of human use, deserves consideration as a candidate drug for suppressing IL-8-dependent lung inflammation in CF.
authors.affiliation: Department of Anatomy, Physiology, and Genetics and Institute for Molecular Medicine, Uniformed Services University School of Medicine, Bethesda, MD 20814, USA.
authors.forename: Meera
authors.initials: M
authors.lastname: Srivastava
authors.forename: Ofer
authors.initials: O
authors.lastname: Eidelman
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Cloud
authors.initials: C
authors.lastname: Paweletz
authors.forename: Hung
authors.initials: H
authors.lastname: Caohuy
authors.forename: QingFeng
authors.initials: Q
authors.lastname: Yang
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Eliahu
authors.initials: E
authors.lastname: Heldman
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Catherine
authors.initials: C
authors.lastname: Jozwik
authors.forename: Bette S
authors.initials: BS
authors.lastname: Pollard
authors.forename: Harvey B
authors.initials: HB
authors.lastname: Pollard
mesh_terms: D002301:Cardiac Glycosides / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D004074:Digitoxin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004848:Epithelium / Q000378:metabolism; D015316:Genetic Therapy; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors; D016209:Interleukin-8 / Q000378:metabolism*; D008168:Lung / Q000378:metabolism
chemical_list: D002301:Cardiac Glycosides; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D016209:Interleukin-8; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004074:Digitoxin