title: Estrogens regulate neuroinflammatory genes via estrogen receptors α and β in the frontal cortex of middle-aged female rats.
abstract: BACKGROUND
  Estrogens exert anti-inflammatory and neuroprotective effects in the brain mainly via estrogen receptors α (ERα) and β (ERβ). These receptors are members of the nuclear receptor superfamily of ligand-dependent transcription factors. This study was aimed at the elucidation of the effects of ERα and ERβ agonists on the expression of neuroinflammatory genes in the frontal cortex of aging female rats.
  
  
  METHODS
  To identify estrogen-responsive immunity/inflammation genes, we treated middle-aged, ovariectomized rats with 17β-estradiol (E2), ERα agonist 16α-lactone-estradiol (16α-LE2) and ERβ agonist diarylpropionitrile (DPN), or vehicle by Alzet minipump delivery for 29 days. Then we compared the transcriptomes of the frontal cortex of estrogen-deprived versus ER agonist-treated animals using Affymetrix Rat230 2.0 expression arrays and TaqMan-based quantitative real-time PCR. Microarray and PCR data were evaluated by using Bioconductor packages and the RealTime StatMiner software, respectively.
  
  
  RESULTS
  Microarray analysis revealed the transcriptional regulation of 21 immunity/inflammation genes by 16α-LE2. The subsequent comparative real-time PCR study analyzed the isotype specific effects of ER agonists on neuroinflammatory genes of primarily glial origin. E2 regulated the expression of sixteen genes, including down-regulation of complement C3 and C4b, Ccl2, Tgfb1, macrophage expressed gene Mpeg1, RT1-Aw2, Cx3cr1, Fcgr2b, Cd11b, Tlr4 and Tlr9, and up-regulation of defensin Np4 and RatNP-3b, IgG-2a, Il6 and ER gene Esr1. Similar to E2, both 16α-LE2 and DPN evoked up-regulation of defensins, IgG-2a and Il6, and down-regulation of C3 and its receptor Cd11b, Ccl2, RT1-Aw2 and Fcgr2b.
  
  
  CONCLUSIONS
  These findings provide evidence that E2, 16α-LE2 and DPN modulate the expression of neuroinflammatory genes in the frontal cortex of middle-aged female rats via both ERα and ERβ. We propose that ERβ is a promising target to suppress regulatory functions of glial cells in the E2-deprived female brain and in various neuroinflammatory diseases.
authors.affiliation: Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony utca 43, Budapest, 1083, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Sárvári
authors.forename: Erik
authors.initials: E
authors.lastname: Hrabovszky
authors.forename: Imre
authors.initials: I
authors.lastname: Kalló
authors.forename: Norbert
authors.initials: N
authors.lastname: Solymosi
authors.forename: Kinga
authors.initials: K
authors.lastname: Tóth
authors.forename: István
authors.initials: I
authors.lastname: Likó
authors.forename: János
authors.initials: J
authors.lastname: Széles
authors.forename: Sándor
authors.initials: S
authors.lastname: Mahó
authors.forename: Béla
authors.initials: B
authors.lastname: Molnár
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Liposits
mesh_terms: D000367:Age Factors; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004660:Encephalitis / Q000503:physiopathology*; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects* / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D046228:Microarray Analysis; D018696:Neuroprotective Agents / Q000494:pharmacology; D009929:Organ Size; D051381:Rats; D017208:Rats, Wistar; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D018696:Neuroprotective Agents; D004958:Estradiol