Gingras S, Simard J
Medical Research Council Group in Molecular Endocrinology, CHUL Research Center and Laval University, Québec City, Québec, Canada.
Endocrinology. 1999 Oct;140(10):4573-84. doi: 10.1210/endo.140.10.7038.
The 3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD) isoenzymes catalyze an essential step in the formation of all classes of active steroid hormones. In humans there are two 3beta-HSD isoenzymes, the type 1 gene being predominantly expressed in the placenta and peripheral tissues, whereas the type 2 gene is the predominant 3beta-HSD expressed in the adrenal glands and gonads. We have recently showed that interleukin (IL)-4 and IL-13 induce 3beta-HSD type 1 gene expression in human breast cancer cell lines as well as in normal human mammary epithelial cells. The present study was designed to investigate whether such a cytokine-induced 3beta-HSD type 1 expression would also be observed in cell types derived from other peripheral sex steroid target tissues. To gain further knowledge about the molecular mechanism of IL-4 action, we have studied whether the induction of 3beta-HSD type 1 expression in IL-4-responsive cell types would always be associated with the activation of Stat6, a member of the Signal Transducers and Activators of Transcription (STAT) gene family. Stat6 is recognized as the principal transcription factor mediating the effects of IL-4. In normal human prostate epithelial cells (PrEC), no 3beta-HSD activity was detectable under basal culture conditions, while exposure to IL-4 or IL-13 caused a potent induction of this activity. This effect results from a rapid induction of 3beta-HSD type 1 messenger RNA levels as determined by Northern blot and RT-PCR analyses. Furthermore, IL-4 and IL-13 also increased 3beta-HSD type 1 gene expression in human HaCaT immortalized keratinocytes, ME-180 cervix cancer cells, HT-29 colon cancer cells as well as in BT-20 and ZR-75-1 breast cancer cells. However, IL-4 and IL-13 failed to modulate the 3beta-HSD type 1 expression in human LnCAP and PC-3 prostate cancer cells, Caco-2 colon cancer cells as well as in JAR and JEG-3 choriocarcinoma cell lines. The DNA-binding activity of Stat6 was activated after a 30-min exposure to IL-4 in PrEC and in all the cell types where IL-4 induced 3beta-HSD expression, but not in those that failed to respond to IL-4. Our data therefore suggest that IL-4 and IL-13 may play a role in the biosynthesis of active sex steroids from the inactive adrenal steroid dehydroepiandrosterone, not only in breast cells but also in various cell types derived from peripheral target tissues, such as normal human prostate epithelial cells, immortalized keratinocytes, as well as colon and cervix cancer cell lines. Our data also demonstrates that the stimulatory effect of IL-4 was always associated with the activation of Stat6, thus supporting the essential role of Stat6 in this induction of 3beta-HSD type 1 gene expression.
3β-羟基类固醇脱氢酶/异构酶（3β-HSD）同工酶催化所有类型活性甾体激素形成过程中的关键步骤。在人类中存在两种3β-HSD同工酶，1型基因主要在胎盘和外周组织中表达，而2型基因是肾上腺和性腺中主要表达的3β-HSD。我们最近发现，白细胞介素（IL）-4和IL-13可诱导人乳腺癌细胞系以及正常人乳腺上皮细胞中1型3β-HSD基因的表达。本研究旨在调查在源自其他外周性甾体靶组织的细胞类型中是否也能观察到这种细胞因子诱导的1型3β-HSD表达。为了进一步了解IL-4作用的分子机制，我们研究了在对IL-4有反应的细胞类型中，1型3β-HSD表达的诱导是否总是与信号转导子和转录激活子（STAT）基因家族成员Stat6的激活相关。Stat6被认为是介导IL-4作用的主要转录因子。在正常人前列腺上皮细胞（PrEC）中，基础培养条件下未检测到3β-HSD活性，而暴露于IL-4或IL-13会导致该活性的强烈诱导。这种效应是由Northern印迹和RT-PCR分析确定的1型3β-HSD信使RNA水平的快速诱导所致。此外，IL-4和IL-13还增加了人HaCaT永生化角质形成细胞、ME-180宫颈癌细胞、HT-29结肠癌细胞以及BT-20和ZR-75-1乳腺癌细胞中1型3β-HSD基因的表达。然而，IL-4和IL-13未能调节人LnCAP和PC-3前列腺癌细胞、Caco-2结肠癌细胞以及JAR和JEG-3绒毛膜癌细胞系中1型3β-HSD的表达。在PrEC以及所有IL-4诱导3β-HSD表达的细胞类型中，暴露于IL-4 30分钟后Stat6的DNA结合活性被激活，但在那些对IL-4无反应的细胞类型中未被激活。因此，我们的数据表明，IL-4和IL-13可能不仅在乳腺细胞中，而且在源自外周靶组织的各种细胞类型中，如正常人前列腺上皮细胞、永生化角质形成细胞以及结肠和宫颈癌细胞系中，在从无活性的肾上腺甾体脱氢表雄酮生物合成活性性甾体中发挥作用。我们的数据还表明，IL-4的刺激作用总是与Stat6的激活相关，从而支持了Stat6在这种1型3β-HSD基因表达诱导中的重要作用。
