en
Scientific article
English

Defective activation of c-Src in cystic fibrosis airway epithelial cells results in loss of tumor necrosis factor-alpha-induced gap junction regulation

Published inThe Journal of biological chemistry, vol. 278, no. 10, p. 8326-8332
Publication date2003
Abstract

Tumor necrosis factor-alpha (TNF-alpha) signaling is central to the transmission of the innate immune response and subsequent activation of the adaptive immune system. The functioning of both systems is required for optimal clearance of pathogens from the airways. In cystic fibrosis (CF), dysfunction of the CF transmembrane conductance regulator (CFTR) is associated with recurrent pulmonary infections despite an intense inflammatory and immune response. We reported recently that TNF-alpha decreased gap junction connectivity in non-CF airway cells, a mechanism that was absent in CF cells expressing the DeltaPhe-508 mutant of CFTR. We have now identified the tyrosine kinase c-Src as a possible pathway between the mediators of inflammation and the gap junction protein connexin43 (Cx43). Indeed, TNF-alpha increased the proportion of activated c-Src in non-CF airway cells. Moreover, pharmacological antagonists and expression in non-CF cells of a dominant negative construct of c-Src prevented Cx43 channel closure by TNF-alpha. Finally, gap junction channel closure was prevented by expression of a Cx43 mutant lacking tyrosine phosphorylation sites for c-Src. Additional experiments showed that activation of c-Src was defective in CF airway cells but rescued in CFTR-corrected CF cells. These data suggest that CFTR dysfunction is associated with altered TNF-alpha signaling, resulting in the persistence of gap junction connectivity in CF airway cells. We propose that altered regulation of c-Src may contribute to the dysregulated inflammatory response that is characteristic of the CF phenotype.

Keywords
  • Cell Line
  • Cystic Fibrosis/metabolism
  • Gap Junctions/physiology
  • Humans
  • Proto-Oncogene Proteins pp60(c-src)/metabolism
  • Trachea/metabolism
  • Tumor Necrosis Factor-alpha/physiology
Citation (ISO format)
HUANG, Song et al. Defective activation of c-Src in cystic fibrosis airway epithelial cells results in loss of tumor necrosis factor-alpha-induced gap junction regulation. In: The Journal of biological chemistry, 2003, vol. 278, n° 10, p. 8326–8332. doi: 10.1074/jbc.M208264200
Main files (1)
Article (Published version)
accessLevelRestricted
Identifiers
ISSN of the journal0021-9258
528views
0downloads

Technical informations

Creation03/07/2013 8:55:00 AM
First validation03/07/2013 8:55:00 AM
Update time03/14/2023 8:06:29 PM
Status update03/14/2023 8:06:29 PM
Last indexation05/02/2024 1:08:44 PM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack