Activation of NF-kappaB in airway epithelial cells is dependent on CFTR trafficking and Cl- channel function.
Activation of NF-kappaB in airway epithelial cells is dependent on CFTR trafficking and Cl- channel function.
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DOI：
10.1152/ajplung.2001.281.1.l71
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发表时间：
2001-07
期刊：
影响因子：
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通讯作者：
Audrey J. Weber;Grace Soong;Ruth Bryan;Shahryar Saba;Alice Prince
中科院分区：
文献类型：
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作者：
Audrey J. Weber;Grace Soong;Ruth Bryan;Shahryar Saba;Alice Prince
多态性白细胞主导的气道炎症是囊性纤维化（CF）肺疾病的主要组成部分，并可能与CF跨膜传导调节因子（CFTR）功能障碍以及感染有关。突变型DeltaF 508 CFTR被误激活，在内质网（ER）中积累，并可能导致“细胞应激”和核因子（NF）-κ B的激活。G551 D突变体也缺乏Cl-通道功能，但CFTR被正常运输。我们比较了CFTR突变对NF-κ B报告基因构建体内源性激活的影响。在转染的中国仓鼠卵巢细胞中，与野生型CFTR或G551 D突变体相比，错配的DeltaF 508等位基因导致NF-κ B活化7倍（P < 0.001）。NF-κ B在9/HTEo-/pCep-R细胞和16 HBE/pcftr反义细胞系中也被激活，这些细胞系缺乏CFTR Cl-通道功能，但不在ER中积累突变蛋白。这种NF-κ B的内源性激活与白细胞介素-8表达升高相关。CFTR Cl-通道活性受损以及由于错误激活的CFTR在ER中积累而导致的细胞应激有助于具有CFTR突变的细胞中NF-κ B的内源性激活。
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.