Suppression of oxidant-induced glutathione synthesis by erythromycin in human bronchial epithelial cells

Background: Macrolide antibiotics have anti-inflammatory effects which are utilized for the treatment of chronic inflammatory airway diseases. Recently, their anti-inflammatory effects have been proposed to be beneficial in patients with chronic obstructive pulmonary disease (COPD). Objectives: Since the molecular mechanisms of anti-inflammatory effects are associated with inhibition of activator protein 1 (AP-1) and nuclear factor (NF)-kappa B, and both are reported to be involved in the expression of gamma-glutamylcysteine synthetase (gamma-GCS), we set out to determine if these drugs influence the oxidant-antioxidant balance in human bronchial epithelial (HBE) cells. Methods: 16HBE cells were preincubated with erythromycin (EM) at different concentrations and times and then exposed to hydrogen peroxide (0.01 mM). Levels of interleukin (IL)-8 and glutathione (GSH), and activity of gamma-GCS and gamma-GCS heavy subunit (gamma-GCS-HS) protein production were assayed. AP-1 and NF-kappa B binding to the 5'-flanking region of IL-8 and gamma-GCS-HS genes was assessed by electrophoretic mobility-shift assay. Results: The increase in IL-8 levels and activity of AP-1 induced by H2O2 were abrogated by preincubation of the cells with EM (5 mu g/ml) for 36 h. We also showed that preincubation with EM for 48 h inhibited H2O2-induced GSH levels, gamma-GCS activity and expression of gamma-GCS-HS, and decreased AP-1 binding to the gamma-GCS-HS 5'-flanking region. Conclusions: The confirmation of antioxidants maintaining enzyme suppression by EM raised concerns on whether this drug could disrupt the oxidant/antioxidant balance during long-term use. These data provide important insights into the treatment of inflammatory lung diseases with macrolide antibiotics. Copyright (C) 2007 S. Karger AG, Basel.