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* Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104;
Division of Immunology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010; and
Center for Immunobiology, Mount Sinai School of Medicine, New York, NY 10029
Estrogen receptor (ER) ligands modulate hemopoiesis and immunity in the normal state, during autoimmunity, and after infection or trauma. Dendritic cells (DC) are critical for initiation of innate and adaptive immune responses. We demonstrate, using cytokine-driven culture models of DC differentiation, that 17-β-estradiol exerts opposing effects on differentiation mediated by GM-CSF and Flt3 ligand, the two cytokines that regulate DC differentiation in vivo. We also show that estradiol acts on the same highly purified Flt3+ myeloid progenitors (MP) to differentially regulate the DC differentiation in each model. In GM-CSF-supplemented cultures initiated from MP, physiological amounts of estradiol promoted differentiation of Langerhans-like DC. Conversely, in Flt3 ligand-supplemented cultures initiated from the same MP, estradiol inhibited cell survival in a dose-dependent manner, thereby decreasing the yield of plasmacytoid and conventional myeloid and lymphoid DC. Experiments with bone marrow cells from ER-deficient mice and the ER antagonist ICI182,780 showed that estradiol acted primarily via ER
to regulate DC differentiation. Thus, depending on the cytokine environment, pathways of ER signaling and cytokine receptor signaling can differentially interact in the same Flt3+ MP to regulate DC development. Because the Flt3 ligand-mediated differentiation pathway is important during homeostasis, and GM-CSF-mediated pathways are increased by inflammation, our data suggest that endogenous or pharmacological ER ligands may differentially affect DC development during homeostasis and disease, with consequent effects on DC-mediated immunity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a grant from the Health Research Program of the Oklahoma Center for the Advancement of Science and Technology.
2 Current address: Department of Pediatrics, University of California, Los Angeles, CA 90095.
3 Address correspondence and reprint requests to Dr. Susan Kovats, Arthritis and Immunology Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104. E-mail address: Susan-Kovats{at}omrf.org
4 Abbreviations used in this paper: DC, dendritic cell; SLE, systemic lupus erythematosus; ER, estrogen receptor; SERM, selective ER modulator; E2, 17-β-estradiol; BM, bone marrow; LC, Langerhans cell; FL, flt3 ligand; MP, myeloid progenitor; CMP, common MP; LP, lymphoid progenitor; CLP, common LP; int, intermediate; SA, streptavidin; FSC, forward scatter; SSC, side scatter; MHCII, MHC class II; QRT PCR, quantitative real-time PCR; GMP, granulocyte/monocyte progenitor; PDC, plasmacytoid DC; MDC, myeloid DC; LDC, lymphoid DC; ELP, early lymphoid progenitor.
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