Estrogens regulate neuroinflammatory genes via estrogen receptors alpha and beta in the frontal cortex of middle-aged female rats

7th Space Interactive

July 23, 2011

Estrogens exert anti-inflammatory and neuroprotective effects in the brain mainly via estrogen receptors alpha (ERalpha) and beta (ERbeta). 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 ERalpha and ERbeta 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 17beta-estradiol (E2), ERalpha agonist 16alpha-lactone-estradiol (16alpha-LE2) and ERbeta 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 16alpha-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 16alpha-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, 16alpha-LE2 and DPN modulate the expression of neuroinflammatory genes in the frontal cortex of middle-aged female rats via both ERalpha and ERbeta.

We propose that ERbeta is a promising target to suppress regulatory functions of glial cells in the E2-deprived female brain and in various neuroinflammatory diseases.

Author: Miklos SarvariErik HrabovszkyImre KalloNorbert SolymosiKinga TothIstvan LikoJanos SzelesSandor MahoBela MolnarZsolt Liposits
Credits/Source: Journal of Neuroinflammation 2011, 8:82

 

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