Lipoxin A4 is a novel estrogen receptor modulator

Ronan Russell, Ilaria Gori, Chiara Pellegrini, Rajesh Kumar, Chahin Achtari, Geraldine O. Canny

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

Abstract

Inflammation is intimately linked with naturally occurring remodeling events in the endometrium. Lipoxins comprise a group of short-lived, non-classic eicosanoids possessing potent anti-inflammatory and proresolution properties. In the present study, we investigated the role of lipoxin A4 (LXA4) in the endometrium and demonstrated that 15-LOX-2, an enzyme necessary for LX biosynthesis, is expressed in this tissue. Our results establish that LXA4 possesses robust estrogenic activity through its capacity to alter ERE transcriptional activity, as well as expression of estrogen- regulated genes, alkaline phosphatase activity, and proliferation in human endometrial epithelial cells. Interestingly, LXA4 also demonstrated antiestrogenic potential, significantly attenuating E2-induced activity. This estrogenic activity was directly mediated through estrogen receptors (ERs). Subsequent investigations determined that the actions of LXA4 are exclusively mediated through ERα and closely mimic those of the potent estrogen 17β-estradiol (E2). In binding assays, LXA4 competed with E2 for ER binding, with an IC50 of 46 nM. Furthermore, LXA4 exhibited estrogenic activity in vivo, increasing uterine wet weight and modulating E2-regulated gene expression. These findings reveal a previously unappreciated facet of LXA4 bioactions, implicating this lipid mediator in novel immunoendocrine crosstalk mechanisms.

Original languageEnglish
Pages (from-to)4326-4337
Number of pages12
JournalFASEB Journal
Volume25
Issue number12
DOIs
Publication statusPublished - Dec 2011
Externally publishedYes

Keywords

  • Eicosanoids
  • Endometrium
  • Estradiol
  • Hormones

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