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

Abstract

Polymorphonuclear leukocyte-dominated airway inflammation is a major component of cystic fibrosis (CF) lung disease and may be associated with CF transmembrane conductance regulator (CFTR) dysfunction as well as infection. Mutant DeltaF508 CFTR is mistrafficked, accumulates in the endoplasmic reticulum (ER), and may cause "cell stress" and activation of nuclear factor (NF)-kappaB. G551D mutants also lack Cl- channel function, but CFTR is trafficked normally. We compared the effects of CFTR mutations on the endogenous activation of an NF-kappaB reporter construct. In transfected Chinese hamster ovary cells, the mistrafficked DeltaF508 allele caused a sevenfold activation of NF-kappaB compared with wild-type CFTR or the G551D mutant (P < 0.001). NF-kappaB was also activated in 9/HTEo-/pCep-R cells and in 16HBE/pcftr antisense cell lines, which lack CFTR Cl- channel function but do not accumulate mutant protein in the ER. This endogenous activation of NF-kappaB was associated with elevated interleukin-8 expression. Impaired CFTR Cl- channel activity as well as cell stress due to accumulation of mistrafficked CFTR in the ER contributes to the endogenous activation of NF-kappaB in cells with the CFTR mutation.

Pulmonary vascular dysfunction in end-stage cystic fibrosis: role of NF- B and endothelin-1

“…We observed that both of them were upregulated. NF-kB is well known to be activated in CF airway epithelial cells and to participate in their dysregulated inflammation [26][27][28]. We extended these findings by demonstrating for the first time to our knowledge a clear overexpression of NFkB in the pulmonary vascular structures of CF subjects who exhibited an impaired response to ACh.…”

Defective Activation of c-Src in Cystic Fibrosis Airway Epithelial Cells Results in Loss of Tumor Necrosis Factor-α-induced Gap Junction Regulation

“…In contrast, this mechanism is defective in CF airway cells but can be rescued by expression of wild-type CFTR (26). These observations, together with other reports (18,(35)(36)(37)(38), suggest that CFTR may interfere with some of the signal transduction pathways initiated through receptor-ligand interactions. In this context, differential regulation of channel activity may represent a model to search for the signaling pathways that are defective in CF cells.…”

Initial interrogation, confirmation and fine mapping of modifying genes: STAT3, IL1B and IFNGR1 determine cystic fibrosis disease manifestation

“…9 Although the mode of inheritance defines CF as a single-gene disorder, its variable course indicates that non-inherited and inherited factors shape the manifestation of the monogenic disease, which has been acknowledged by several research groups with an investigation of CF-modifying genes. The disease is characterized by a proinflammatory state, 10 which has been described in-vitro in cell systems, [11][12][13][14][15][16] using a murine model 17 and was confirmed mostly, [18][19][20][21] albeit not exclusively, 22,23 in ex-vivo material studied from CF patients. Consequently, several studied candidate genes were derived from the field of immunity, immunology and host defense such as the cytokines IL8, [24][25][26] IL1B 25,26 and TGFB1.…”