Estradiol promotes functional responses in inflammatory and steady-state dendritic cells through differential requirement for activation function-1 of estrogen receptor α

J Immunol. 2013 Jun 1;190(11):5459-70. doi: 10.4049/jimmunol.1203312. Epub 2013 Apr 26.


17β-Estradiol (E2) has been shown to regulate GM-CSF- or Flt3 ligand-driven dendritic cell (DC) development through estrogen receptor (ER) α signaling in myeloid progenitors. ERα regulates transcription of target genes through two distinct activation functions (AFs), AF-1 and AF-2, whose respective involvement varies in a cell type- or tissue-specific manner. In this study, we investigated the role of ERα AFs in the development and effector functions of inflammatory DCs, steady-state conventional DCs, and plasmacytoid DCs (pDC), using mouse lacking either AF-1 or AF-2. In agreement with previous works, we showed that E2 fostered the differentiation and effector functions of inflammatory DCs through ERα-dependent upregulation of IFN regulatory factor (IRF)-4 in GM-CSF-stimulated myeloid progenitors. Interestingly, whereas AF-1 was required for early IRF-4 upregulation in DC precursors, it was dispensable to enhance IRF-4 expression in differentiated DCs to a level compatible with the development of the more functional Ly6C(-) CD11b(+) DC subset. Presence of E2 had no effect on progenitors from either knock-in mice with 7-aa deletion in helix 12 of ERα, lacking AF-2, or ERα(-/-) mice. By contrast, in Flt3 ligand-driven DC differentiation, activation of AF-1 domain was required to promote the development of more functionally competent conventional DCs and pDCs. Moreover, lack of ERα AF-1 blunted the TLR7-mediated IFN-α response of female pDCs in vivo. Thus, our study demonstrates that ERα uses AF-1 differently in steady-state and inflammatory DC lineages to regulate their innate functions, suggesting that selective ER modulators could be used to target specific DC subsets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD11 Antigens / metabolism
  • Cell Differentiation
  • Dendritic Cells / cytology
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism*
  • Estradiol / metabolism*
  • Estrogen Receptor alpha / chemistry
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism
  • Male
  • Membrane Proteins / pharmacology
  • Mice
  • Mice, Transgenic
  • Phenotype
  • Protein Interaction Domains and Motifs*
  • Signal Transduction
  • Toll-Like Receptors / metabolism


  • CD11 Antigens
  • Estrogen Receptor alpha
  • Interferon Regulatory Factors
  • Membrane Proteins
  • Toll-Like Receptors
  • flt3 ligand protein
  • interferon regulatory factor-4
  • Estradiol
  • Granulocyte-Macrophage Colony-Stimulating Factor