RRC ID 43936
Author Veillat V, Sengers V, Metz CN, Roger T, Leboeuf M, Mailloux J, Akoum A.
Title Macrophage migration inhibitory factor is involved in a positive feedback loop increasing aromatase expression in endometriosis.
Journal Am J Pathol
Abstract Immune-endocrine interplay may play a major role in the pathogenesis of endometriosis. In the present study, we have investigated the interaction between macrophage migration inhibitory factor (MIF), a major pro-inflammatory and growth-promoting factor markedly expressed in active endometriotic lesions, and estradiol (E(2)) in ectopic endometrial cells. Our data showed a significant increase of MIF protein secretion and mRNA expression in endometriotic cells in response to E(2). MIF production was blocked by Fulvestrant, an estrogen receptor (ER) antagonist, and induced by ERα and ERβ selective agonists propyl-pyrazole-triol (PPT) and diarylpropionrile (DPN), respectively, thus demonstrating a specific receptor-mediated effect. Cell transfection with MIF promoter construct showed that E(2) significantly stimulates MIF promoter activity. Interestingly, our data further revealed that MIF reciprocally stimulates aromatase protein and mRNA expression via a posttranscriptional mRNA stabilization mechanism, that E(2) itself can upregulate aromatase expression, and that inhibition of endogenous MIF, using MIF specific siRNA, significantly inhibits E(2)-induced aromatase. Thus, the present study revealed the existence of a local positive feedback loop by which estrogen acts directly on ectopic endometrial cells to upregulate the expression of MIF, which, in turn, displays the capability of inducing the expression of aromatase, the key and rate-limiting enzyme for estrogen synthesis. Such interplay may have a considerable impact on the development of endometriosis.
Volume 181(3)
Pages 917-27
Published 2012-9-1
DOI 10.1016/j.ajpath.2012.05.018
PII S0002-9440(12)00422-1
PMID 22759564
MeSH Adult Aromatase / biosynthesis Aromatase / genetics* Endometriosis / enzymology* Endometriosis / genetics* Endometriosis / pathology Enzyme Induction / drug effects Estradiol / pharmacology Estrogen Receptor alpha / metabolism Estrogen Receptor beta / metabolism Feedback, Physiological* / drug effects Female Gene Expression Regulation / drug effects Humans Intramolecular Oxidoreductases / genetics Intramolecular Oxidoreductases / metabolism* Keratins / metabolism Macrophage Migration-Inhibitory Factors / genetics Macrophage Migration-Inhibitory Factors / metabolism* Neprilysin / metabolism Promoter Regions, Genetic / genetics RNA Stability / drug effects RNA Stability / genetics RNA, Messenger / genetics RNA, Messenger / metabolism Stromal Cells / drug effects Stromal Cells / metabolism Stromal Cells / pathology Vimentin / metabolism
IF 3.491
Times Cited 23
Human and Animal Cells KGN(RCB1154)