| First Author | Seillet C | Year | 2013 |
| Journal | J Immunol | Volume | 190 |
| Issue | 11 | Pages | 5459-70 |
| PubMed ID | 23626011 | Mgi Jnum | J:204866 |
| Mgi Id | MGI:5543571 | Doi | 10.4049/jimmunol.1203312 |
| Citation | Seillet C, et al. (2013) Estradiol promotes functional responses in inflammatory and steady-state dendritic cells through differential requirement for activation function-1 of estrogen receptor alpha. J Immunol 190(11):5459-70 |
| abstractText | 17beta-Estradiol (E2) has been shown to regulate GM-CSF- or Flt3 ligand-driven dendritic cell (DC) development through estrogen receptor (ER) alpha signaling in myeloid progenitors. ERalpha 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 ERalpha 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 ERalpha-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 ERalpha, lacking AF-2, or ERalpha(-/-) 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 ERalpha AF-1 blunted the TLR7-mediated IFN-alpha response of female pDCs in vivo. Thus, our study demonstrates that ERalpha 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. |
