Estradiol selectively regulates innate immune function by polarized human uterine epithelial cells in culture

Mucosal Immunol. 2008 Jul;1(4):317-25. doi: 10.1038/mi.2008.20. Epub 2008 May 14.


The goal of this study was to examine the role of E(2) in regulating innate immune protection by human uterine epithelial cells (UECs). Recognizing that UECs produce cytokines and chemokines to recruit and activate immune cells as well as viral and bacterial antimicrobials, we sought to examine the effect of E(2) on constitutive and Toll-like receptor (TLR) agonist (lipopolysaccharide (LPS) and poly (I:C))-induced immune responses. The secretion by polarized UECs in culture of interleukin (IL)-6, macrophage inhibitory factor (MIF), and secretory leukocyte protease inhibitor (SLPI) was examined as well as the mRNA expression of human beta-defensin-2 (HBD2), tumor necrosis factor (TNF)-alpha, IL-8, and nuclear factor (NF)-kB. When incubated with E(2) for 24-48 h, we found that E(2) stimulated UEC secretion of SLPI (fourfold) and mRNA expression of HBD2 (fivefold). Moreover, when antibacterial activity in UEC secretions was measured using Staphylococcus aureus, E(2) increased the secretion of soluble factor(s) with antibacterial activity. In contrast, E(2) had no effect on constitutive secretion of proinflammatory cytokines and chemokines by UECs but completely inhibited LPS- and poly (I:C)-induced secretion of MIF, IL-6, and IL-8. Estradiol also reversed the stimulatory effects of IL-1beta on mRNA expression of TNF-alpha, IL-8, and NF-kB by 85, 95, and 70%, respectively. As SLPI is known to inhibit NF-kB expression, these findings suggest that E(2) inhibition of proinflammatory cytokines may be mediated through SLPI regulation of NF-kB. Overall, these findings indicate that the production of cytokines, chemokines, and antimicrobials by UECs are differentially regulated by E(2). Further, it suggests that with E(2) regulation, epithelial cells that line the uterine cavity have evolved immunologically to be sensitive to viral and bacterial infections as well as the constraints of procreation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Polarity / physiology*
  • Cells, Cultured
  • Cytokines / immunology*
  • Cytokines / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism*
  • Estradiol / pharmacology*
  • Estradiol / physiology
  • Female
  • Humans
  • Immunity, Innate*
  • Interleukin-6 / metabolism
  • Interleukin-8 / metabolism
  • Intramolecular Oxidoreductases / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophage Migration-Inhibitory Factors / metabolism
  • NF-kappa B / metabolism
  • Secretory Leukocyte Peptidase Inhibitor / metabolism
  • Staphylococcus aureus / physiology
  • Toll-Like Receptors / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • Uterus / cytology*
  • beta-Defensins / metabolism


  • Cytokines
  • DEFB4A protein, human
  • Interleukin-6
  • Interleukin-8
  • Lipopolysaccharides
  • Macrophage Migration-Inhibitory Factors
  • NF-kappa B
  • SLPI protein, human
  • Secretory Leukocyte Peptidase Inhibitor
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • beta-Defensins
  • Estradiol
  • Intramolecular Oxidoreductases
  • MIF protein, human