Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from fibrosis lung epithelial cells

Meera Srivastava, Ofer Eidelman, Jian Zhang, Cloud Paweletz, Hung Caohuy, Qing Feng Yang, Kenneth A. Jacobson, Eliahu Heldman, Wei Huang, Catherine Jozwik, Bette S. Pollard, Harvey B. Pollard

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

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-κB (IκBα). IκBα phosphorylation is a required step in the activation of the NF-κB 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.

Original languageEnglish
Pages (from-to)7693-7698
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number20
DOIs
StatePublished - 18 May 2004

ASJC Scopus subject areas

  • General

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