Selective estrogen receptor-β agonists repress transcription of proinflammatory genes

In addition to their role in the development and function of the reproductive system, estrogens have significant anti-inflammatory properties. Although both estrogen receptors (ERs) can mediate anti-inflammatory actions, ER beta is a more desirable therapeutic target because ER alpha mediates the proliferative effects of estrogens on the mammary gland and uterus. In fact, selective ER beta agonists have beneficial effects in preclinical models involving inflammation without causing growth-promoting effects on the uterus or mammary gland. However, their mechanism of action is unclear. The purpose of this study was to use microarray analysis to determine whether ER beta-selective compounds produce their anti-inflammatory effects by repressing transcription of proinflammatory genes. We identified 49 genes that were activated by TNF-alpha in human osteosarcoma U2OS cells expressing ER beta. Estradiol treatment significantly reduced the activation by TNF-alpha on 18 genes via ER beta or ER alpha. Most repressed genes were inflammatory genes, such as TNF-alpha, IL-6, and CSF2. Three ER beta-selective compounds, ERB-041, WAY-202196, and WAY-214156, repressed the expression of these and other inflammatory genes. ERB-041 was the most ER beta-selective compound, whereas WAY-202196 and WAY-214156 were the most potent. The ER beta-selective compounds repressed inflammatory genes by recruiting the coactivator, SRC-2. ERB-041 also repressed cytokine genes in PBMCs, demonstrating that ER beta-selective estrogens have anti-inflammatory properties in immune cells. Our study suggests that the anti-inflammatory effects of ERB-041 and other ER beta-selective estrogens in animal models are due to transcriptional repression of proinflammatory genes. These compounds might represent a new class of drugs to treat inflammatory disorders.