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, ERβ is a more desirable therapeutic target because ERα mediates the proliferative effects of estrogens on the mammary gland and uterus. In fact, selective ERβ 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 ERβ-selective compounds produce their anti-inflammatory effects by repressing transcription of proinflammatory genes. We identified 49 genes that were activated by TNF-α in human osteosarcoma U2OS cells expressing ERβ. Estradiol treatment significantly reduced the activation by TNF-α on 18 genes via ERβ or ERα. Most repressed genes were inflammatory genes, such as TNF-α, IL-6, and CSF2. Three ERβ-selective compounds, ERB-041, WAY-202196, and WAY-214156, repressed the expression of these and other inflammatory genes. ERB-041 was the most ERβ-selective compound, whereas WAY-202196 and WAY-214156 were the most potent. The ERβ-selective compounds repressed inflammatory genes by recruiting the coactivator, SRC-2. ERB-041 also repressed cytokine genes in PBMCs, demonstrating that ERβ-selective estrogens have anti-inflammatory properties in immune cells. Our study suggests that the anti-inflammatory effects of ERB-041 and other ERβ-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.