17β-Estradiol Inhibits IL-8 in Cystic Fibrosis by Up-Regulating Secretory Leucoprotease Inhibitor

Rationale: An unexplained gender gap is observed in cystic fibrosis (CF). Females have poorer lung function, decreased survival, and earlier Pseudomonas colonization. Objectives: To evaluate the effect of 17 beta-estradiol (E-2) on CF bronchial epithelial cells in vitro and in vivo. Methods: On exposure of CFBE41o-cultures to physiological concentrations of E-2, there was a significant dose-dependent inhibition of IL-8 release induced by toll-like receptor agonists, CF bronchoalveolar lavage fluid, or Pseudomonas-conditioned media. Estrogen receptor (ER)-alpha and -beta expression was quantified in cell lines and bronchial brushings from CF and non-CF patients. Measurements and Main Results: Both receptors were expressed in vitro and in vivo, although ER beta expression was significantly higher in CF. Using ER isoform-specific agonists and antagonists, we established that ER beta mediates the inhibition of CF bronchoalveolar lavage fluid induced IL-8 release. We also showed that secretory leucoprotease inhibitor gene expression and protein localization to the nucleus increased in response to E-2. Secretory leucoprotease inhibitor knockdown abrogated the inhibitory effects of E-2. Conclusions: E-2 inhibits IL-8 release by ER beta in CF bronchial epithelial cells through up-regulation of secretory leucoprotease inhibitor, inhibition of nuclear factor (NF)-kappa B, and IL-8 gene expression. These data implicate a novel anti-inflammatory mechanism for E-2 in females with CF, which predisposes to infection and colonization. This could, in part, account for the observed gender dichotomy in CF.