Abstract
BackgroundGlucocorticoids (GCs) are a first-line treatment for asthma for their anti-inflammatory effects, but they also hinder the repair of airway epithelial injury. The anti-inflammatory protein GC-induced leucine zipper (GILZ) is reported to inhibit the activation of the mitogen-activated protein kinase (MAPK)-extracellular-signal-regulated kinase (ERK) signaling pathway, which promotes the repair of airway epithelial cells around the damaged areas. We investigated whether the inhibition of airway epithelial repair imposed by the GC dexamethasone (DEX) is mediated by GILZ.MethodsWe tested the effect of DEX on the expressions of GILZ mRNA and GILZ protein and the MAPK-ERK signaling pathway in human airway epithelial cells, via RT-PCR and Western blot. We further evaluated the role of GILZ in mediating the effect of DEX on the MAPK-ERK signaling pathway and in airway epithelium repair by utilizing small-interfering RNAs, MTT, CFSE labeling, wound-healing and cell migration assays.ResultsDEX increased GILZ mRNA and GILZ protein levels in a human airway epithelial cell line. Furthermore, DEX inhibited the phosphorylation of Raf-1, Mek1/2, Erk1/2 (components of the MAPK-ERK signaling pathway), proliferation and migration. However, the inhibitory effect of DEX was mitigated in cells when the GILZ gene was silenced.ConclusionsThe inhibition of epithelial injury repair by DEX is mediated in part by activation of GILZ, which suppressed activation of the MAPK-ERK signaling pathway, proliferation and migration. Our study implicates the involvement of DEX in this process, and furthers our understanding of the dual role of GCs.
Highlights
Asthma is a chronic inflammatory airway disorder accompanied by airway epithelial cell damage
We investigated whether the inhibition of airway epithelial repair imposed by the GC dexamethasone (DEX) is mediated by GC-induced leucine zipper (GILZ), and associated changes in the mitogen-activated protein kinase (MAPK)-extracellular-signal-regulated kinase (ERK) signaling pathway and cellular proliferation and migration
We found that DEX (10 mM) significantly induced mRNA levels of GILZ starting at 6 h, and levels continued to increase 24 h after treatment compared to the untreated control cells (P,0.05), as determined by reverse transcription PCR (RT-PCR) (Figure 1A)
Summary
Asthma is a chronic inflammatory airway disorder accompanied by airway epithelial cell damage. There is evidence that in asthma the repair process is fundamentally flawed, and is associated with activation of the epithelial-mesenchymal trophic unit and growth factors that cause pathological airway remodeling [2]. Glucocorticoids (GCs) are a first-line treatment for asthma for their anti-inflammatory effects, but they hinder the repair of airway epithelial injury. The anti-inflammatory protein GC-induced leucine zipper (GILZ) is reported to inhibit the activation of the mitogen-activated protein kinase (MAPK)-extracellular-signal-regulated kinase (ERK) signaling pathway, which promotes the repair of airway epithelial cells around the damaged areas. We investigated whether the inhibition of airway epithelial repair imposed by the GC dexamethasone (DEX) is mediated by GILZ
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