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(American Journal of Pathology. 2001;158:1775-1784.)
© 2001 American Society for Investigative Pathology

Regular Articles

Regulation of Gap Junctional Communication by a Pro-Inflammatory Cytokine in Cystic Fibrosis Transmembrane Conductance Regulator-Expressing but Not Cystic Fibrosis Airway Cells

Marc Chanson^*, Pierre-Yves Berclaz, Isabelle Scerri^*, Tecla Dudez^*, Kara Wernke-Dollries, Lara Pizurki^*, Andrea Pavirani, Michael A. Fiedler and Susanne Suter^*

From the Department of Pediatrics,^*
Laboratory of Clinical Investigation III, University Hopitals, Geneva, Switzerland; the Division of Pulmonary Medicine,
Children’s Hospital Medical Center, Cincinnati, Ohio; and Transgene SA,
Strasbourg, France

Airway inflammation is orchestrated by cell-cell interactions involving soluble mediators and cell adhesion molecules. Alterations in the coordination of the multicellular process of inflammation may play a major role in the chronic lung disease state of cystic fibrosis (CF). The aim of this study was to determine whether direct cell-cell interactions via gap junctional communication is affected during the inflammatory response of the airway epithelium. We have examined the strength of intercellular communication and the activation of nuclear factor-B (NF-B) in normal (non-CF) and CF human airway cell lines stimulated with tumor necrosis factor- (TNF-). TNF- induced maximal translocation of NF-B into the nucleus of non-CF as well as CF airway cells within 20 minutes. In non-CF cells, TNF- progressively decreased the extent of intercellular communication. In contrast, gap junctional communication between CF cells exposed to TNF- remained unaltered. CF results from mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Interestingly, transfer of wild-type CFTR into CF cells by adenovirus-mediated infection was associated with the recovery of TNF--induced uncoupling. These results suggest that expression of functional CFTR is necessary for regulation of gap junctional communication by TNF-. Gap junction channels close during the inflammatory response, therefore limiting the intercellular diffusion of signaling molecules, and thereby the recruitment of neighboring cells. Defects in this mechanism may contribute to the excessive inflammatory response of CF airway epithelium.

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