Expression of Wild-Type CFTR Suppresses NF-κB-Driven Inflammatory Signalling

Expression of Wild-Type CFTR Suppresses NF-κB-Driven Inflammatory Signalling

Mairi J. Hunter, Kate J. Treharne, Alexandra K. Winter, Diane M. Cassidy, Stephen Land, Anil Meht

LoS ONE 5(7): e11598. doi:10.1371/journal.pone.0011598


Background
Mutation of the cystic fibrosis transmembrane-conductance regulator (CFTR) causes cystic fibrosis (CF) but not all CF aspects can easily be explained by deficient ion transport. CF-inflammation provides one example but its pathogenesis remains controversial. Here, we tested the simple but fundamental hypothesis that wild-type CFTR is needed to suppress NF-κB activity.

Methodology/Principal Findings
In lung epithelial (H441) and engineered (H57) cell lines; we report that inflammatory markers are significantly suppressed by wild-type CFTR. Transient-transfection of wild-type CFTR into CFTR-naïve H441 cells, dose-dependently down-regulates both basal and Tumour Necrosis Factor-α evoked NF-κB activity when compared to transfection with empty vector alone (p5). This effect was also observed in CFTR-naïve H57-HeLa cells which stably express a reporter of NF-κB activity, confirming that the CFTR-mediated repression of inflammation was not due to variable reporter gene transfection efficiency. In contrast, H57 cells transfected with a control cyano-fluorescent protein show a significantly elevated basal level of NF-κB activity above control. Initial cell seeding density may be a critical factor in mediating the suppressive effects of CFTR on inflammation as only at a certain density (1×105 cells/well) did we observe the reduction in NF-κB activity. CFTR channel activity may be necessary for this suppression because the CFTR specific inhibitor CFTRinh172 significantly stimulates NF-κB activity by ~30% in CFTR expressing 16HBE14o− cells whereas pharmacological elevation of cyclic-AMP depresses activity by ~25% below baseline.

Conclusions/Significance
These data indicate that CFTR has inherent anti-inflammatory properties. We propose that the hyper-inflammation found in CF may arise as a consequence of disrupted repression of NF-κB signalling which is normally mediated by CFTR. Our data therefore concur with in vivo and in vitro data from Vij and colleagues which highlights CFTR as a suppressor of basal inflammation acting through NF-κB, a central hub in inflammatory signalling.

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