Regulation of gap junctional communication by a pro-inflammatory cytokine in cystic fibrosis transmembrane conductance regulator-expressing but not cystic fibrosis airway cells

Airway inflammation is orchestrated by cell-cell interactions involving sol uble 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 w as to determine whether direct cell-cell interactions via gap junctional co mmunication is affected during the inflammatory response of the airway epit helium, we have examined the strength of intercellular communication and th e activation of nuclear factor-kappaB (NF-kappaB) in normal (non-CF) and CF human airway cell lines stimulated with tumor necrosis factor-alpha (TNF-a lpha). TNF-alpha induced maximal translocation of NF-kappaB into the nucleu s of non-CF as well as CF airway cells within 20 minutes. In non-CF cells, TNF-alpha progressively decreased the extent of intercellular communication . In contrast, gap junctional communication between CF cells exposed to TNF -alpha remained unaltered. CF results from mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Interestingly, transfer o f wild-type CFTR into CF cells by adenovirus-mediated infection was associa ted with the recovery of TNF-alpha -induced uncoupling. These results sugge st that expression of functional CFTR is necessary for regulation of gap ju nctional communication by TNF-alpha. Gap junction channels close during the inflammatory response, therefore limiting the intercellular diffusion of s ignaling molecules, and thereby the recruitment of neighboring cells. Defec ts in this mechanism may contribute to the excessive inflammatory response of CF airway epithelium.