Up-regulation of AMP-activated kinase by dysfunctional cystic fibrosis transmembrane conductance regulator in cystic fibrosis airway epithelial cells mitigates excessive inflammation
Up-regulation of AMP-activated kinase by dysfunctional cystic fibrosis transmembrane conductance regulator in cystic fibrosis airway epithelial cells mitigates excessive inflammation
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DOI：
10.1074/jbc.m511029200
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发表时间：
2006-02-17
影响因子：
4.8
通讯作者：
Pilewski, JM
中科院分区：
文献类型：
--
作者：
Hallows, KR;Fitch, AC;Pilewski, JM
amp活化激酶（AMPK）是一种普遍存在的代谢传感器，可抑制囊性纤维化（CF）跨膜传导调节因子（CFTR）。为了确定CFTR是否在气道上皮中相互调节AMPK的功能，以及这种调节是否参与肺部炎症，我们比较了AMPK的定位、表达、活性和细胞代谢谱在CF和非CF原代人支气管上皮（HBE）细胞中CFTR状态的功能。与非CF HBE细胞相比，CF细胞的AMPK染色更大、更分散，AMPK活性也高于形态匹配的非CF HBE细胞。未分化的细胞[AMP]/[ATP]比值高于已分化的非cf细胞，这与AMPK活性相关。然而，这个核苷酸比例并不能预测分化的CF细胞中AMPK的活性。抑制非CF细胞中的通道活性不会影响AMPK活性或代谢状态，但在CF细胞中表达功能性CFTR会降低AMPK活性，但不会影响细胞[AMP]/[ATP]。因此，CF细胞中CFTR功能性表达的缺乏和通道活性的不丧失似乎上调了CF HBE细胞中AMPK的活性，可能是通过对上游调节途径的非代谢作用。与表达cftr的野生型永生化CF支气管上皮（CFBE）细胞相比，表达CFBE的δ f508cftr细胞具有更高的AMPK活性，分泌更多的肿瘤坏死因子- α和白细胞介素IL-6和IL-8。在野生型和δ f508表达细胞中，AMPK激活进一步抑制炎症介质的分泌，表明CF气道细胞中AMPK激活是一种减少炎症的适应性反应。我们提出，激活CF气道AMPK的治疗可能有助于减少过度的气道炎症，这是CF发病率的主要原因。
AMP-activatedkinase (AMPK) is a ubiquitous metabolic sensor that inhibits the cystic fibrosis (CF) transmembrane conductance regulator (CFTR). To determine whether CFTR reciprocally regulates AMPK function in airway epithelia and whether such regulation is involved in lung inflammation, AMPK localization, expression, and activity and cellular metabolic profiles were compared as a function of CFTR status in CF and non-CF primary human bronchial epithelial (HBE) cells. As compared with non-CF HBE cells, CF cells had greater and more diffuse AMPK staining and had greater AMPK activity than their morphologically matched non-CF counterparts. The cellular [AMP]/[ATP] ratio was higher in undifferentiated than in differentiated non-CF cells, which correlated with AMPK activity under these conditions. However, this nucleotide ratio did not predict AMPK activity in differentiating CF cells. Inhibiting channel activity in non-CF cells did not affect AMPK activity or metabolic status, but expressing functional CFTR in CF cells reduced AMPK activity without affecting cellular [AMP]/[ATP]. Therefore, lack of functional CFTR expression and not loss of channel activity in CF cells appears to up-regulate AMPK activity in CF HBE cells, presumably through non- metabolic effects on upstream regulatory pathways. Compared with wild-type CFTR-expressing immortalized CF bronchial epithelial (CFBE) cells, Delta F508CFTR-expressing CFBE cells had greater AMPK activity and greater secretion of tumor necrosis factor-alpha and the interleukins IL-6 and IL-8. Further pharmacologic AMPK activation inhibited inflammatory mediator secretion in both wild type- and Delta F508-expressing cells, suggesting that AMPK activation in CF airway cells is an adaptive response that reduces inflammation. We propose that therapies to activate AMPK in the CF airway may be beneficial in reducing excessive airway inflammation, a major cause of CF morbidity.