Activation of NF-kappa B in airway epithelial cells is dependent on CFTR trafficking and Cl- channel function

Polymorphonuclear leukocyte-dominated airway inflammation is a major compon ent of cystic fibrosis (CF) lung disease and may be associated with CF tran smembrane conductance regulator (CFTR) dysfunction as well as infection. Mu tant Delta F508 CFTR is mistrafficked, accumulates in the endoplasmic retic ulum (ER), and may cause "cell stress" and activation of nuclear factor (NF )-kappaB. G551D mutants also lack Cl- channel function, but CFTR is traffic ked normally. We compared the effects of CFTR mutations on the endogenous a ctivation of an NF-kappaB reporter construct. In transfected Chinese hamste r ovary cells, the mistrafficked Delta F508 allele caused a sevenfold activ ation of NF-kappaB compared with wild-type CFTR. or the G551D mutant (P < 0 .001). NF-<kappa>B was also activated in 9/HTEo /pCep-R cells and in 16HBE/ pcftr antisense cell lines, which lack CFTR Cl- channel function hut do not accumulate mutant protein in the ER. This endogenous activation of NF-kapp aB was associated with elevated interleukin-8 expression. Impaired CFTR Cl- channel activity as well as cell stress due to accumulation of mistraffick ed CFTR in the ER contributes to the endogenous activation of NF-kappaB in cells with the CFTR mutation.