17Beta-estradiol inhibits IL-8 in cystic fibrosis by up-regulating secretory leucoprotease inhibitor

Am J Respir Crit Care Med. 2010 Jul 1;182(1):62-72. doi: 10.1164/rccm.201001-0053OC. Epub 2010 Apr 8.


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 17beta-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 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).

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Cells, Cultured
  • Cystic Fibrosis / metabolism*
  • Epithelial Cells / metabolism*
  • Estradiol / physiology*
  • Estrogen Receptor beta / physiology
  • Female
  • Humans
  • Interleukin-8 / metabolism*
  • Male
  • NF-kappa B / physiology
  • Respiratory Mucosa / metabolism
  • Secretory Leukocyte Peptidase Inhibitor / metabolism*
  • Sex Factors
  • Up-Regulation
  • Young Adult


  • CXCL8 protein, human
  • Estrogen Receptor beta
  • Interleukin-8
  • NF-kappa B
  • Secretory Leukocyte Peptidase Inhibitor
  • Estradiol