title: Macrophage migration inhibitory factor is involved in a positive feedback loop increasing aromatase expression in endometriosis.
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.
authors: Laboratory of Reproductive Endocrinology, Research Center, Hospital of Saint-François of Assisi CHUQ, Québec, Canada.
authors: Véronique
authors: V
authors: Veillat
authors: Valérie
authors: V
authors: Sengers
authors: Christine N
authors: CN
authors: Metz
authors: Thierry
authors: T
authors: Roger
authors: Mathieu
authors: M
authors: Leboeuf
authors: Jacques
authors: J
authors: Mailloux
authors: Ali
authors: A
authors: Akoum
mesh_terms: D000328:Adult; D001141:Aromatase / Q000096:biosynthesis / Q000235:genetics*; D004715:Endometriosis / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D004790:Enzyme Induction / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D007633:Keratins / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D015260:Neprilysin / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D020871:RNA Stability / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014746:Vimentin / Q000378:metabolism
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; D014746:Vimentin; D004958:Estradiol; D007633:Keratins; D001141:Aromatase; D015260:Neprilysin; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human