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: Miklós Sárvári, Erik Hrabovszky, Imre Kalló, Norbert Solymosi, Kinga Tóth, István Likó, János Széles, Sándor Mahó, Béla Molnár, Zsolt Liposits
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 8 Pg. 82 (Jul 20 2011) ISSN: 1742-2094 [Electronic] England
• PMID: 21774811 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Estrogen Receptor alpha
• Estrogen Receptor beta
• Neuroprotective Agents
• Estradiol

Topics

• Age Factors
• Animals
• Body Weight (drug effects)
• Encephalitis (physiopathology)
• Estradiol (pharmacology)
• Estrogen Receptor alpha (agonists, genetics, metabolism)
• Estrogen Receptor beta (agonists, genetics, metabolism)
• Female
• Frontal Lobe (drug effects, physiology)
• Gene Expression Profiling
• Gene Expression Regulation (drug effects, immunology)
• Microarray Analysis
• Neuroprotective Agents (pharmacology)
• Organ Size
• Rats
• Rats, Wistar
• Uterus (anatomy & histology, drug effects)