Regulation of 3β-hydroxysteroid dehydrogenase type 1 and type 2 gene expression and function in the human ovarian surface epithelium by cytokines
Regulation of 3β-hydroxysteroid dehydrogenase type 1 and type 2 gene expression and function in the human ovarian surface epithelium by cytokines
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DOI：
10.1093/molehr/gap022
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发表时间：
2009-06-01
影响因子：
4
通讯作者：
Mason, J. Ian
中科院分区：
文献类型：
--
作者：
Papacleovoulou, Georgia;Hogg, Kirsten;Mason, J. Ian
人卵巢表面上皮细胞（hOSE）是一个围绕卵巢的鳞状至立方状层。由于排卵诱导的炎症，hOSE经历损伤和修复周期，这是与上皮性卵巢癌（EOC）的发展相关的事件。局部产生的类固醇介导炎症反应。3 β-羟基类固醇脱氢酶（3 β-HSD）驱动孕激素和雄激素的内分泌产生，可能影响细胞存活和增殖。因此，我们研究了hOSE中3 β-HSD沿着下游类固醇信号传导的调节。培养的原代hOSE细胞的双重免疫荧光证实了3 β-HSD蛋白白细胞介素（IL）的表达。用IL-1 α处理原代细胞以模拟排卵相关炎症，可抑制3 β-HSD 1的表达并刺激3 β-HSD 2的mRNA表达（P < 0.001），而不影响总的3 β-HSD蛋白和活性或雄激素或孕激素受体（PR）mRNA水平。相反，IL-4作为排卵后愈合细胞因子的替代物增加了3 β-HSD转录物、总蛋白和活性（P < 0.01）。IL-4还抑制雄激素受体的表达（P < 0.01），而不影响PR的表达，从而潜在地维持卵巢表面的孕酮生物合成及其潜在的信号传导。3 β-HSD蛋白在诊断为EOC的妇女的原发性腹水中是免疫可检测的，但两种mRNA转录相对于正常细胞减少（P < 0.05）。值得注意的是，这种差异被IL-4治疗抵消（P < 0.01）。我们的结论是，刺激IL-4可能是生理相关的排卵后卵巢愈合，并提出了一种新的治疗策略，在卵巢癌中的孕酮相关的细胞凋亡的激活。此外，我们的研究结果表明，衰减3 β-HSD表达EOC，虽然需要进一步的研究来确认。
The human ovarian surface epithelium (hOSE) is a squamous-to-cuboidal layer that surrounds the ovary. hOSE undergoes injury and repair cycles as a result of ovulation-induced inflammation, an event relevant to the development of epithelial ovarian cancer (EOC). Locally produced steroids mediate the response to inflammation. 3 beta-Hydroxysteroid dehydrogenase (3 beta-HSD) drives the intracrine generation of progestogens and androgens that potentially affect cell survival and proliferation. We therefore investigated the regulation of 3 beta-HSD along with downstream steroid signalling in hOSE. Double immunofluorescence of cultured primary hOSE cells confirmed the expression of 3 beta-HSD protein Interleukin (IL). IL-1 alpha treatment of primary cells to mimic ovulation-associated inflammation suppressed 3 beta-HSD1 expression and stimulated 3 beta-HSD2 mRNA (P < 0.001), without affecting total 3 beta-HSD protein and activity or androgen or progesterone receptor (PR) mRNA levels. Conversely, IL-4 as a proxy for a post-ovulatory healing cytokine increased both 3 beta-HSD transcripts, total protein and activity (P < 0.01). IL-4 also suppressed androgen receptor expression (P < 0.01) without affecting that of the PR, thereby potentially sustaining both progesterone biosynthesis and its underlying signalling in the ovarian surface. 3 beta-HSD protein was immunodetectable in primary ascites of women who were diagnosed with EOC but both mRNA transcripts were diminished relative to normal cells (P < 0.05). Notably, this difference was countered by IL-4 treatment (P < 0.01). We conclude that stimulation by IL-4 could be physiologically relevant to post-ovulatory ovarian healing and suggest a novel therapeutic strategy for the activation of progesterone-associated apoptosis in ovarian cancer. Also, our results suggest an attenuation of 3 beta-HSD expression in EOC although further studies are required for confirmation.