科研之友
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摘要
Airway epithelial NE-kappa B activation is observed in asthmatic subjects and is a cause of airway inflammation in mouse models of allergic asthma. Combination therapy with inhaled short acting beta(2)-agonists and corticosteroids significantly improves lung function and reduces inflammation in asthmatic subjects. Corticosteroids operate through a number of mechanisms to potently inhibit NE-kappa B activity. Since beta(2)-agonists can induce expression of 11 beta-HSD1, which converts inactive 11-keto corticosteroids into active 11-hydroxy corticosteroids, thereby potentiating the effects of endogenous glucocorticoids, we examined whether this mechanism is involved in the inhibition of NE-kappa B activation induced by the beta-agonist albuterol in airway epithelial cells. Treatment of transformed murine Club cells (MTCC) with (R)-albuterol (levalbuterol), but not with (S)- or a mixture of (R + S)- (racemic) albuterol, augmented mRNA expression of 11 beta-HSD1. MTCC were stably transfected with luciferase (luc) reporter constructs under transcriptional regulation by NE-kappa B (NF-kappa B/luc) or glucocorticoid response element (GRE/luc) consensus motifs. Stimulation of NF-kappa B/luc MTCC with lipopolysaccharide (LPS) or tumor necrosis factor-alpha (INF alpha) induced luc activity, which was inhibited by pretreatment with (R)-, but not (S)- or racemic albuterol. Furthermore, pretreatment of GRE/luc MTCC with (R)-, but not with (S)- or racemic albuterol, augmented 11-keto corticosteroid (cortisone) induced luc activity, which was diminished by the 11 beta-HSD inhibitor glycyrrhetinic acid (18 beta-GA), indicating that there was a conversion of inactive 11-keto to active 11-hydroxy corticosteroids. LPS- and TNF alpha-induced NF-kappa B/luc activity was diminished in MTCC cells treated with a combination of cortisone and (R)albuterol, an effect that was inhibited by 18 beta-GA. Finally, pretreatment of MTCC cells with the combination of cortisone and (R)-albuterol diminished LPS- and INF alpha-induced pro-inflammatory cytokine production to an extent similar to that of dexamethasone. These results demonstrate that levalbuterol augments expression of 11 beta-HSD1 in airway epithelial cells, reducing LPS-induced NE-kappa B transcriptional activity and pro-inflammatory cytokine production through the conversion of inactive 11-keto corticosteroids into the active 11-hydroxy form in this cell type.
- 出版日期2015-1-12
