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

Abstract

An unexplained gender gap is observed in cystic fibrosis (CF). Females have poorer lung function, decreased survival, and earlier Pseudomonas colonization. To evaluate the effect of 17beta-estradiol (E(2)) on CF bronchial epithelial cells in vitro and in vivo. 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. Both receptors were expressed in vitro and in vivo, although ERbeta expression was significantly higher in CF. Using ER isoform-specific agonists and antagonists, we established that ERbeta 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). E(2) inhibits IL-8 release by ERbeta in CF bronchial epithelial cells through up-regulation of secretory leucoprotease inhibitor, inhibition of nuclear factor (NF)-kappaB, 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.