Interaction of the estrogen receptors with the Fas ligand promoter in human monocytes.
The predominance of autoimmune diseases among women suggests that estrogen may modulate immune function. Monocytes and macrophages are important in initiating, maintaining, and resolving inflammatory responses through cell-signaling molecules, which control immune cell survival. One important mechanism of cell survival is mediated by the Fas/Fas ligand (FasL) system. In this study, the link between estrogen, monocytes/macrophages, and the Fas/FasL system was investigated. Estrogen treatment increased FasL expression in monocytes through the binding of the estrogen receptors (ER) to the estrogen recognizing elements and AP-1 motifs present at the FasL promoter. Furthermore, estrogen induced apoptosis in monocytes expressing ERbeta, but not in monocyte-differentiated macrophages expressing ERalpha. The expression of either ERalpha or ERbeta and their response to estrogen in monocytes was found to be dependent on the their stage of cell differentiation. Previously, we have shown that estrogen replacement therapy in postmenopausal women decreased the number of circulating monocytes. In this study, we have characterized the molecular mechanism by which estrogen regulates monocytes homeostasis. These findings indicate that estrogen may regulate immune cell survival through the Fas/FasL system. There is biological relevance to these findings in view of studies showing that accumulation of activated monocytes is involved in the pathogenesis of conditions such as vasculititis, arteriosclerosis, and rheumatoid arthritis.
Mor
Gil
G
Department of Obstetrics and Gynecology, School of Medicine, Yale University, New Haven, CT 06520, USA. Gil.Mor@yale.edu
Sapi
Eva
E
Abrahams
Vikki M
VM
Rutherford
Thomas
T
Song
Joon
J
Hao
Xiao-Ying
XY
Muzaffar
Saeher
S
Kohen
Fortune
F
D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001483:Base Sequence; D001665:Binding Sites / Q000276:immunology; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D003001:Cloning, Molecular; D004789:Enzyme Activation / Q000276:immunology; D004958:Estradiol / Q000494:pharmacology; D053222:Fas Ligand Protein; D006801:Humans; D008024:Ligands; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000276:immunology*; D020033:Protein Isoforms / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000502:physiology; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000502:physiology; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D019014:fas Receptor / Q000378:metabolism*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D019014:fas Receptor; D004958:Estradiol; D020169:Caspases