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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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