4.5 Article

Dexamethasone inhibits the action of TNF on ENaC expression and activity

Publisher

AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00511.2005

Keywords

Na+ channel; lung; transepithelial current; inflammation; steroid

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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.

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