Selective estrogen receptor-beta 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, 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.
Cvoro
Aleksandra
A
Department of Obstetrics, Gynecology, and Reproductive Sciences and Center for Reproductive Sciences, Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143-0556, USA.
Tatomer
Deirdre
D
Tee
Meng-Kian
MK
Zogovic
Tatjana
T
Harris
Heather A
HA
Leitman
Dale C
DC
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics; D015536:Down-Regulation; D047629:Estrogen Receptor beta / Q000819:agonists*; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D010080:Oxazoles / Q000494:pharmacology; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; C478102:ERB 041; D047629:Estrogen Receptor beta; D010080:Oxazoles; D020845:Selective Estrogen Receptor Modulators; D014409:Tumor Necrosis Factor-alpha