title: An ADIOL-ERβ-CtBP transrepression pathway negatively regulates microglia-mediated inflammation.
abstract: Microglia and astrocytes play essential roles in the maintenance of homeostasis within the central nervous system, but mechanisms that control the magnitude and duration of responses to infection and injury remain poorly understood. Here, we provide evidence that 5-androsten-3β,17β-diol (ADIOL) functions as a selective modulator of estrogen receptor (ER)β to suppress inflammatory responses of microglia and astrocytes. ADIOL and a subset of synthetic ERβ-specific ligands, but not 17β-estradiol, mediate recruitment of CtBP corepressor complexes to AP-1-dependent promoters, thereby repressing genes that amplify inflammatory responses and activate Th17 T cells. Reduction of ADIOL or ERβ expression results in exaggerated inflammatory responses to TLR4 agonists. Conversely, the administration of ADIOL or synthetic ERβ-specific ligands that promote CtBP recruitment prevents experimental autoimmune encephalomyelitis in an ERβ-dependent manner. These findings provide evidence for an ADIOL/ERβ/CtBP-transrepression pathway that regulates inflammatory responses in microglia and can be targeted by selective ERβ modulators.
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Saijo
authors.forename: Jana G
authors.initials: JG
authors.lastname: Collier
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Li
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D015114:Androstenediol / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000517:prevention & control; D047629:Estrogen Receptor beta / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D004268:DNA-Binding Proteins; D047629:Estrogen Receptor beta; D016760:Proto-Oncogene Proteins c-fos; D015114:Androstenediol; D015067:17-Hydroxysteroid Dehydrogenases; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein