Dexamethasone inhibits the action of TNF on ENaC expression and activity

Abstract

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 ∼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 α, β, and γENaC mRNA expression. When the cells were pretreated for 24 h with TNF before cotreatment, dexamethasone was still able to increase αENaC mRNA expression to 1.8-fold above control values. However, in these conditions, β and γENaC mRNA expression was reduced to 47% and 14%, respectively. The potential role of TNF and dexamethasone on αENaC promoter activity was tested in A549 alveolar epithelial cells. TNF decreased luciferase (Luc) expression by ∼25% in these cells, indicating that the strong diminution of αENaC 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 αENaC 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.

Dexamethasone decreases the transmesothelial electrical resistance of the parietal and visceral pleura

“…-K ? ATPase) on the plasma membrane of epithelial cells as well as by up-regulation of their activity [22][23][24]. However, translocation of these transporters is known to occur at a later time period than the 5-10 min in which we observed the decrease in R TM in our study.…”

Dexamethasone acutely accelerates pleural fluid absorption in mice hydrothoraces

“…In both cases, the quoted effect was attributed to up-regulation of ion transporting channels on the mesothelial plasma membrane of pleural cells. The above may provide an explanation of our findings regarding the acceleration of the pleural fluid absorption in our system, which may be related with corticosteroid-induced up-regulation of ion transport [7][8][9][10][11] in mesothelial cells.…”

“…/H ? exchanger) in epithelial cells [7][8][9][10][11]. These proteins are thought to participate in pleural fluid removal from the pleural space [12,13].…”

“…/H ? exchanger) [7][8][9][10][11], which, in turn, have been implicated in pleural fluid absorption [12,13]. We thus hypothesized that corticosteroids increase the absorption rate of isosmotic hydrothoraces in mice.…”

Cycloheximide and lipopolysaccharide downregulate αENaC mRNA via different mechanisms in alveolar epithelial cells

“…Glucocorticoids and cAMP (9,10,21,25) increase ENaC expression and activity, whereas factors involved in lung inflammation and lesions, such as interleukin (IL)-1␤ (45), , tumor necrosis factor-␣ (TNF-␣) (10,11), and transforming growth factor-␤ (TGF-␤) (17), downregulate them. The complex control of ␣ENaC gene expression is mediated via transcriptional activity of its promoter (7,9,10,36,45) but could also entail posttranscriptional regulation of transcript stability (11).…”