BACKGROUND Over the past fifteen years, we have demonstrated that cortisol and dehydroepiandrosterone (DHEA) have opposite effects on the regulation of protein kinase C (PKC) activity in the context of the immune system. The anti-glucocorticoid effect of DHEA is also related to the regulation of splicing of the glucocorticoid receptor (GR), promoting the expression of GRβ isoform, which acts as a negative dominant form on GRα activity. Moreover, it is very well known that DHEA can be metabolized to androgens like testosterone, dihydrotestosterone (DHT), and its metabolites 3α-diol and 3β-diol, which exert their function through the binding of the androgen receptor (AR). Based on this knowledge, and on early observation that castrated animals show results similar to those observed in old animals, the purpose of this study is to investigate the role of androgens and the androgen receptor (AR) in DHEA-induced expression of the PKC signaling molecule RACK1 (Receptor for Activated C Kinase 1) and cytokine production in monocytes. RESULTS Here we demonstrated the ability of the anti-androgen molecule, flutamide, to counteract the stimulatory effects of DHEA on RACK1 and GRβ expression, and cytokine production. In both THP-1 cells and human peripheral blood mononuclear cells (PBMC), flutamide blocked the effects of DHEA, suggesting a role of the AR in these effects. As DHEA is not considered a direct AR agonist, we investigated the metabolism of DHEA in THP-1 cells. We evaluated the ability of testosterone, DHT, and androstenedione to induce RACK1 expression and cytokine production. In analogy to DHEA, an increase in RACK1 expression and in LPS-induced IL-8 and TNF-α production was observed after treatment with these selected androgens. Finally, the silencing of AR with siRNA completely prevented DHEA-induced RACK1 mRNA expression, supporting the idea that AR is involved in DHEA effects. CONCLUSIONS We demonstrated that the conversion of DHEA to active androgens, which act via AR, is a key mechanism in the effect of DHEA on RACK1 expression and monocyte activation. This data supports the existence of a complex hormonal balance in the control of immune modulation, which can be further studied in the context of immunosenescence and endocrinosenescence.

中文翻译：

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雄激素在dhea诱导的单核细胞中rack1表达和细胞因子调节中的作用。

背景技术在过去的十五年中，我们已经证明皮质醇和脱氢表雄酮（DHEA）在免疫系统中对蛋白激酶C（PKC）活性的调节具有相反的作用。DHEA的抗糖皮质激素作用还与糖皮质激素受体（GR）的剪接调控，促进GRβ亚型的表达有关，后者是GRα活性的负显性形式。此外，众所周知，DHEA可以代谢为雄激素，例如睾丸激素，二氢睾丸激素（DHT）及其代谢物3α-二醇和3β-二醇，它们通过与雄激素受体（AR）结合而发挥其功能。基于这些知识，以及根据早期观察，cast割的动物显示出的结果与在老动物中观察到的结果相似，这项研究的目的是研究雄激素和雄激素受体（AR）在DHEA诱导的PKC信号分子RACK1（活化C激酶1受体）表达和单核细胞中细胞因子产生中的作用。结果在这里，我们证明了抗雄激素分子氟他胺有能力抵消DHEA对RACK1和GRβ表达以及细胞因子产生的刺激作用。在THP-1细胞和人外周血单个核细胞（PBMC）中，氟他胺均阻断了DHEA的作用，表明AR在这些作用中的作用。由于DHEA不被认为是直接的AR激动剂，因此我们研究了THEA-1细胞中DHEA的代谢。我们评估了睾丸激素，DHT和雄烯二酮诱导RACK1表达和细胞因子产生的能力。类似于DHEA，用这些选定的雄激素治疗后，观察到RACK1表达的增加以及LPS诱导的IL-8和TNF-α的产生。最后，用siRNA沉默AR可完全阻止DHEA诱导的RACK1 mRNA表达，从而支持AR参与DHEA效应的观点。结论我们证明了DHEA通过AR作用向活性雄激素的转化是DHEA对RACK1表达和单核细胞活化作用的关键机制。该数据支持在控制免疫调节中存在复杂的激素平衡，可以在免疫衰老和内分泌衰老的情况下进一步研究。支持AR参与DHEA效应的观点。结论我们证明，DHEA通过AR起作用而转化为活性雄激素，这是DHEA对RACK1表达和单核细胞活化作用的关键机制。该数据支持在控制免疫调节中存在复杂的激素平衡，可以在免疫衰老和内分泌衰老的情况下进一步研究。支持AR参与DHEA效应的观点。结论我们证明了DHEA通过AR作用向活性雄激素的转化是DHEA对RACK1表达和单核细胞活化作用的关键机制。该数据支持在控制免疫调节中存在复杂的激素平衡，可以在免疫衰老和内分泌衰老的情况下进一步研究。