Estrogen receptor signaling promotes dendritic cell differentiation by increasing expression of the transcription factor IRF4.
During inflammation, elevated granulocyte macrophage-colony-stimulating factor (GM-CSF) directs the development of new dendritic cells (DCs). This pathway is influenced by environmental factors, and we previously showed that physiologic levels of estradiol, acting through estrogen receptor alpha (ERalpha), promote the GM-CSF-mediated differentiation of a CD11b(+) DC subset from myeloid progenitors (MPs). We now have identified interferon regulatory factor 4 (IRF4), a transcription factor induced by GM-CSF and critical for CD11b(+) DC development in vivo, as a target of ERalpha signaling during this process. In MPs, ERalpha potentiates and sustains GM-CSF induction of IRF4. Furthermore, retroviral delivery of the Irf4 cDNA to undifferentiated ERalpha(-/-) bone marrow cells restored the development of the estradiol/ERalpha-dependent DC population, indicating that an elevated amount of IRF4 protein substitutes for ERalpha signaling. Thus at an early stage in the MP response to GM-CSF, ERalpha signaling induces an elevated amount of IRF4, which leads to a developmental program underlying CD11b(+) DC differentiation.
Carreras
Esther
E
Arthritis & Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Turner
Sean
S
Frank
Mark Barton
MB
Knowlton
Nicholas
N
Osban
Jeanette
J
Centola
Michael
M
Park
Chae Gyu
CG
Simmons
Amie
A
Alberola-Ila
José
J
Kovats
Susan
S
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D050835:Interferon Regulatory Factors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D012190:Retroviridae; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014161:Transduction, Genetic; D000099218:Interferon Regulatory Factor-4
D039481:CD11b Antigen; D004958:Estradiol; D047628:Estrogen Receptor alpha; D004967:Estrogens; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D050835:Interferon Regulatory Factors; D000099218:Interferon Regulatory Factor-4