Interleukin-4 and Prostaglandin E2 Synergistically Up-Regulate 3β-Hydroxysteroid Dehydrogenase Type 2 in Endometrioma Stromal Cells
Context:Endometriosis is a chronic inflammatory disease in which immune response and production of estrogen in endometriotic tissues are involved in the development of the disease. Prostaglandin E2 (PGE2) stimulates aromatase (P450arom) expression in endometrioma stromal cells (ESCs) and increases the production of estrogens. On the other hand, an accumulating amount of evidence suggests that IL-4, a typical Th2 cytokine, plays important roles in the disease.Objective:The objective of the investigation was to study the effect of IL-4 on the expression of 3β-hydroxysteroid dehydrogenase (HSD3B2), a pivotal enzyme for estrogen production, in ESCs.Design, Patients, and Main Outcome Measures:ESCs were isolated from ovarian endometrioma tissues and cultured with IL-4 and PGE2. CP-690550, a Janus protein tyrosine kinase 3 inhibitor, and HSD3B2 small interfering RNA were added to the culture. Gene expression of HSD3B2 and P450arom was examined by quantitative RT-PCR. Dehydroepiandrosterone (DHEA) was added to the culture, and then the combined enzyme activity of HSD3B2, which converts DHEA to androstenedione, and P450arom, which converts androstenedione to estrone, was examined by measuring estrone concentration in the supernatants with a specific enzyme immunoassay.Results:IL-4 increased the expression of HSD3B2 mRNA in a dose-dependent manner. CP-650550 inhibited the IL-4-induced increase in HSD3B2 mRNA expression. PGE2 also increased the expression of HSD3B2 mRNA, and the combination of IL-4 and PGE2 synergistically increased the expression of HSD3B2 mRNA. IL-4 had no effect on the expression of P450arom mRNA, whereas PGE2 increased the expression of P450arom mRNA. Although PGE2 alone increased the production of estrone from DHEA, the combination of IL-4 and PGE2 significantly augmented the production of estrone from DHEA. The enhanced production of estrone by the combination of IL-4 and PGE2 was inhibited by CP-690550 and HSD3B2 small interfering RNA.Conclusions:IL-4 in combination with PGE2 may enhance estrogen production in endometriotic tissues, implying an elaborate mechanism that Th2 immune response augments inflammation-dependent progression of the disease.
Available from: Vincent Anaf
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ABSTRACT: Context Endometriosis is a common gynecologic condition characterized by an important inflammatory process mediated by the prostaglandin pathway. Oral contraceptives (OC) are the treatment of choice for symptomatic endometriotic women. However the effects of OC use and prostaglandin pathway in endometriotic women is actually still unknown. Objective To investigate the expression of prostaglandin pathway key genes in endometriotic tissue, affected or not by hormonal therapy, as compared to healthy endometrial tissue. Design A comparative laboratory study Setting Tertiary-care university hospital Patient(s) Seventy-six women, with (n=46) and without (n=30) histologically proven endometriosis. Main Outcome Measure(s) Prostaglandin-endoperoxidase synthase (PTGS)1, PTGS2, prostaglandin E receptor (PTGER)1, PTGER2, PTGER3 and PTGER4 mRNA levels in endometrium of disease-free women and in eutopic and ectopic endometrium of endometriosis-affected women. PTGS2 expression was further investigated by immunohistochemistry, using specific monoclonal antibodies. PTGS2 expression was analyzed at mRNA and protein levels and correlated with taking hormonal treatment. Result(s) PTGS2 expression was significantly increased in eutopic and ectopic endometrium as compared to healthy tissue (induction of 9.6 and 6.3-fold, respectively; p=0.001). PTGS2 immunoreactivity increased gradually from normal endometrium to eutopic and ectopic endometrium (h-score of 96.7 ± 55.0, 128.3 ± 66.1 and 226.7 ± 62.6 respectively, p<0.001). PTGER2, PTGER3 and PTGER4 expression increased significantly and gradually from normal to eutopic and ectopic endometrium whereas PTGER1 remained unchanged. Patients under hormonal treatment had a higher PTGS2 expression at transcriptional and protein levels as compared to those without treatment (p= 0.002 and p= 0.025 respectively). Conclusion(s) Prostaglandin pathway is strongly deregulated in eutopic and ectopic endometrium of women suffering from endometriosis for the benefit of an increased PTGS2 expression. We show for the first time that hormonal treatment appears to enhance even more PTGS2 expression. These results contribute to explain why medical treatment could fail to control endometriosis progression.
Available from: Alexander Zhavoronkov
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ABSTRACT: Endometriosis is a common and painful condition affecting women of reproductive age. While the underlying pathophysiology is still largely unknown, much advancement has been made in understanding the progression of the disease. In recent years, a great deal of research has focused on non-invasive diagnostic tools, such as biomarkers, as well as identification of potential therapeutic targets. In this article, we will review the etiology and cellular mechanisms associated with endometriosis as well as the current diagnostic tools and therapies. We will then discuss the more recent genomic and proteomic studies and how these data may guide development of novel diagnostics and therapeutics. The current diagnostic tools are invasive and current therapies primarily treat the symptoms of endometriosis. Optimally, the advancement of "-omic" data will facilitate the development of non-invasive diagnostic biomarkers as well as therapeutics that target the pathophysiology of the disease and halt, or even reverse, progression. However, the amount of data generated by these types of studies is vast and bioinformatics analysis, such as we present here, will be critical to identification of appropriate targets for further study.
Available from: Jian-Jun Wei
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ABSTRACT: In endometriosis, stromal and epithelial cells from the endometrium form extra-uterine lesions and persist in response to estrogen (E2) and prostaglandin E2 (PGE2). Stromal cells produce excessive quantities of estrogen and PGE2 in a feed-forward manner. However, it is unknown how estrogen stimulates cell proliferation and survival for the establishment and persistence of disease. Previous studies suggest that estrogen receptor β (ERβ) is strikingly overexpressed in endometriotic stromal cells. Thus, we integrated genome-wide ERβ binding data from previously published studies in breast cells and gene expression profiles in human endometriosis and endometrial tissues (total sample number=81) and identified RAS-like, estrogen-regulated, growth inhibitor (RERG) as an ERβ target. Estradiol potently induced RERG mRNA and protein levels in primary endometriotic stromal cells. Chromatin immunoprecipitation demonstrated E2-induced enrichment of ERβ at the RERG promoter region. PGE2 via PKA phosphorylated RERG and enhanced nuclear translocation of RERG. RERG induced proliferation of primary endometriotic cells. Overall, we demonstrated that E2/ERβ and PGE2, integrate at RERG leading to increased endometriotic cell proliferation and represents novel a candidate for therapeutic intervention.
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