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 ΔF508 CFTR is mistrafficked, accumulates in the endoplasmic reticulum (ER), and may cause "cell stress" and activation of nuclear factor (NF)-κB. 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-κB reporter construct. In transfected Chinese hamster ovary cells, the mistrafficked ΔF508 allele caused a sevenfold activation of NF-κB compared with wild-type CFTR or the G551D mutant (P < 0.001). NF-κB 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-κB 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-κB in cells with the CFTR mutation.
| Original language | English (US) |
|---|---|
| Journal | American Journal of Physiology - Lung Cellular and Molecular Physiology |
| Volume | 281 |
| Issue number | 1 25-1 |
| State | Published - 2001 |
| Externally published | Yes |
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Keywords
- Chloride channel
- Cystic fibrosis transmembrane conductance regulator
- Inflammatory response
- Intracellular calcium
- Mitogen-activated protein kinase
- Nuclear factor-κB
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Cell Biology
- Physiology
- Physiology (medical)
Cite this
Activation of NF-κB in airway epithelial cells is dependent on CFTR trafficking and Cl- channel function. / Weber, Adam J.; Soong, Grace; Bryan, Ruth; Saba, Shahryar; Prince, Alice.
In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 281, No. 1 25-1, 2001.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Activation of NF-κB in airway epithelial cells is dependent on CFTR trafficking and Cl- channel function
AU - Weber, Adam J.
AU - Soong, Grace
AU - Bryan, Ruth
AU - Saba, Shahryar
AU - Prince, Alice
PY - 2001
Y1 - 2001
N2 - 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 ΔF508 CFTR is mistrafficked, accumulates in the endoplasmic reticulum (ER), and may cause "cell stress" and activation of nuclear factor (NF)-κB. 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-κB reporter construct. In transfected Chinese hamster ovary cells, the mistrafficked ΔF508 allele caused a sevenfold activation of NF-κB compared with wild-type CFTR or the G551D mutant (P < 0.001). NF-κB 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-κB 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-κB in cells with the CFTR mutation.
AB - 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 ΔF508 CFTR is mistrafficked, accumulates in the endoplasmic reticulum (ER), and may cause "cell stress" and activation of nuclear factor (NF)-κB. 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-κB reporter construct. In transfected Chinese hamster ovary cells, the mistrafficked ΔF508 allele caused a sevenfold activation of NF-κB compared with wild-type CFTR or the G551D mutant (P < 0.001). NF-κB 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-κB 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-κB in cells with the CFTR mutation.
KW - Chloride channel
KW - Cystic fibrosis transmembrane conductance regulator
KW - Inflammatory response
KW - Intracellular calcium
KW - Mitogen-activated protein kinase
KW - Nuclear factor-κB
UR - http://www.scopus.com/inward/record.url?scp=0034816052&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034816052&partnerID=8YFLogxK
M3 - Article
C2 - 11404248
AN - SCOPUS:0034816052
VL - 281
JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology
JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology
SN - 1931-857X
IS - 1 25-1
ER -