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