Dexamethasone inhibits the action of TNF on ENaC expression and activity
Dexamethasone inhibits the action of TNF on ENaC expression and activity
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DOI：
10.1152/ajplung.00511.2005
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发表时间：
2006-12-01
影响因子：
4.9
通讯作者：
Berthiaume, Yves
中科院分区：
文献类型：
--
作者：
Dagenais, Andre;Frechette, Rosalie;Berthiaume, Yves
地塞米松可抑制肿瘤坏死因子对ENaC表达和活性的影响。Am J Physiol肺细胞分子生理学291：L1220-L1231,2006。2006年7月28日首次出版；DOI：10.1152/ajplung。00511.2005。-我们已报道，肿瘤坏死因子是一种存在于多种肺部病理中的促炎细胞因子，可使肺泡上皮细胞上皮细胞钠离子通道(ENaC)的表达和活性降低70%。由于地塞米松已被证明可以上调ENaC的mRNA表达，并众所周知地下调促炎基因，我们测试了它是否可以缓解肿瘤坏死因子对ENaC表达和活性的影响。在与肿瘤坏死因子共同处理时，我们发现地塞米松逆转了肿瘤坏死因子的抑制作用，并上调了α、β和γENaC基因的表达。在用肿瘤坏死因子处理细胞24 h后，地塞米松仍能使细胞中的γ-ENaC基因表达增加至对照组的1.8倍。然而，在这些条件下，β和γENaC mRNA的表达分别降低到47%和14%。在A549肺泡上皮细胞中检测肿瘤坏死因子和地塞米松对αENaC启动子活性的潜在作用。在这些细胞中，肿瘤坏死因子使荧光素酶(Luc)的表达降低约25%，这表明Gamma ENaC mRNA的强烈降低可能与转录后事件有关。地塞米松使LUC在细胞中的表达增加了5倍，并使启动子活性增加了2.77倍。除了对αENaC基因表达的影响外，地塞米松还能够将阿米洛利敏感电流和肿瘤坏死因子处理的细胞的液体清除能力维持在正常范围内。以上结果提示，地塞米松可减轻肿瘤坏死因子对肺泡上皮细胞ENaC表达和活性的下调作用。
Dexamethasone inhibits the action of TNF on ENaC expression and activity. Am J Physiol Lung Cell Mol Physiol 291: L1220 - L1231, 2006. First published July 28, 2006; doi:10.1152/ajplung. 00511.2005. - We have reported that TNF, a proinflammatory cytokine present in several lung pathologies, decreases the expression and activity of the epithelial Na+ channel (ENaC) by similar to 70% in alveolar epithelial cells. Because dexamethasone has been shown to upregulate ENaC mRNA expression and is well known to downregulate proinflammatory genes, we tested if it could alleviate the effect of TNF on ENaC expression and activity. In cotreatment with TNF, we found that dexamethasone reversed the inhibitory effect of TNF and upregulated alpha, beta, and gamma ENaC mRNA expression. When the cells were pretreated for 24 h with TNF before cotreatment, dexamethasone was still able to increase gamma ENaC mRNA expression to 1.8- fold above control values. However, in these conditions, beta and gamma ENaC mRNA expression was reduced to 47% and 14%, respectively. The potential role of TNF and dexamethasone on alpha ENaC promoter activity was tested in A549 alveolar epithelial cells. TNF decreased luciferase (Luc) expression by similar to 25% in these cells, indicating that the strong diminution of gamma ENaC mRNA must be related to posttranscriptional events. Dexamethasone raised Luc expression by fivefold in the cells and augmented promoter activity by 2.77-fold in cotreatment with TNF. In addition to its effect on alpha ENaC gene expression, dexamethasone was able to maintain amiloride-sensitive current as well as the liquid clearance abilities of TNF-treated cells within the normal range. All these results suggest that dexamethasone alleviates the downregulation of ENaC expression and activity in TNF-treated alveolar epithelial cells.