Sun K, Yang K, Challis J R
MRC Group in Fetal and Neonatal Health and Development, Department of Physiology, University of Toronto, Ontario, Canada.
Biol Reprod. 1998 Jun;58(6):1379-84. doi: 10.1095/biolreprod58.6.1379.
Human placenta and fetal membranes contain two types of 11beta-hydroxysteroid dehydrogenase (11beta-HSD). 11Beta-HSD1 interconverts cortisol and cortisone and is the predominant isoform found in the fetal membranes. 11Beta-HSD2, which predominates in the placenta syncytiotrophoblast, converts cortisol to cortisone. It has been proposed that placental 11beta-HSD protects the fetus from high levels of maternal glucocorticoids. In this study, cultured term human placental and chorionic trophoblasts were used to examine the regulation of 11beta-HSD1 and 11beta-HSD2 activities and mRNA expression by progesterone, estrogen, and activators of adenylate cyclase (forskolin) and protein kinase C (phorbol 12-myristate 13-acetate, PMA). Placental trophoblast displayed mainly type 2 oxidase activities. 11Beta-HSD in the chorionic trophoblast was exclusively an 11beta-HSD1 reductase. Progesterone (0.001-1 microM) inhibited 11beta-HSD2 activity in a dose-dependent fashion. Inhibition of endogenous progesterone production with trilostane enhanced 11beta-HSD2 activity. The inhibitory effect of progesterone on 11beta-HSD2 activity was not reversed by the progesterone receptor antagonists RU-486 or onapristone. Progesterone (1 microM) also reduced levels of 11beta-HSD2 mRNA, an effect that was attenuated by both RU-486 and onapristone. Estradiol (1 microM) inhibited type 2 oxidase activity as well. Activation of adenylate cyclase by forskolin (100 microM) up-regulated both 11beta-HSD2 activity and mRNA expression; there was no effect of PMA (1 microM) on 11beta-HSD2. 11Beta-HSD1 reductase activity was unaffected by progesterone, estrogen, forskolin, or PMA in either the placental or chorionic trophoblasts. We conclude that both progesterone and estrogen are inhibitors of 11beta-HSD2 activity in term human placenta in vitro. Levels of 11beta-HSD2 activity and mRNA are increased by activation of the cAMP pathway. Progesterone also suppresses levels of 11beta-HSD2 mRNA.
人胎盘和胎膜含有两种类型的11β-羟基类固醇脱氢酶（11β-HSD）。11β-HSD1可使皮质醇和可的松相互转化，是胎膜中主要的同工型。11β-HSD2主要存在于胎盘合体滋养层，可将皮质醇转化为可的松。有人提出胎盘11β-HSD可保护胎儿免受母体高水平糖皮质激素的影响。在本研究中，使用培养的足月人胎盘和绒毛膜滋养层细胞来检测孕酮、雌激素、腺苷酸环化酶激活剂（福斯可林）和蛋白激酶C激活剂（佛波醇12-肉豆蔻酸酯13-乙酸酯，PMA）对11β-HSD1和11β-HSD2活性及mRNA表达的调节作用。胎盘滋养层主要表现出2型氧化酶活性。绒毛膜滋养层中的11β-HSD完全是11β-HSD1还原酶。孕酮（0.001 - 1μM）以剂量依赖性方式抑制11β-HSD2活性。用曲洛司坦抑制内源性孕酮生成可增强11β-HSD2活性。孕酮受体拮抗剂RU-486或奥那司酮不能逆转孕酮对11β-HSD2活性的抑制作用。孕酮（1μM）还降低了11β-HSD2 mRNA水平，RU-486和奥那司酮均可减弱这一作用。雌二醇（1μM）也抑制2型氧化酶活性。福斯可林（100μM）激活腺苷酸环化酶可上调11β-HSD2活性和mRNA表达；PMA（1μM）对11β-HSD2无影响。在胎盘或绒毛膜滋养层细胞中，11β-HSD1还原酶活性不受孕酮、雌激素、福斯可林或PMA的影响。我们得出结论，在体外，孕酮和雌激素均是足月人胎盘11β-HSD2活性的抑制剂。cAMP途径的激活可增加11β-HSD2活性和mRNA水平。孕酮还可抑制11β-HSD2 mRNA水平。
