期刊
JOURNAL OF IMMUNOLOGY
卷 190, 期 11, 页码 5459-5470出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1203312
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资金
- Agence Nationale de la Recherche [ANR-PHYSIO-06-010, ANR-09-GENOPAT-008]
- Arthritis Fondation Courtin
- Association pour la Recherche sur le Cancer
- Comite Haute-Garonne de la Ligue Nationale Contre le Cancer
- Conseil Regional Midi-Pyrenees
- Association pour la Recherche sur la Sclerose en Plaques
17 beta-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. ER alpha 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 ER alpha 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 ER alpha-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 ER alpha, lacking AF-2, or ER alpha(-/-) 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 ER alpha AF-1 blunted the TLR7-mediated IFN-alpha response of female pDCs in vivo. Thus, our study demonstrates that ER alpha 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.
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