Laboratory of Toxicology, Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università degli Studi di Milano, Milan, Italy.
Department of Drug Sciences - Pharmacology Unit, University of Pavia, Viale Taramelli 14, Pavia, 27100 Italy.
Immun Ageing. 2016 May 29;13:20. doi: 10.1186/s12979-016-0075-y. eCollection 2016.
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.
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.
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.
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也与糖皮质激素受体（GR）剪接的调节有关，促进 GRβ 同工型的表达，GRβ 同工型作为 GRα 活性的负显性形式发挥作用。此外，众所周知，DHEA 可以代谢为雄激素，如睾酮、二氢睾酮（DHT）及其代谢物 3α-二醇和 3β-二醇，它们通过雄激素受体（AR）的结合发挥作用。基于这一知识，以及早期观察到去势动物表现出类似于老年动物观察到的结果，本研究旨在研究雄激素和雄激素受体（AR）在 DHEA 诱导的 PKC 信号分子 RACK1（激活 C 激酶 1 的受体）和单核细胞细胞因子产生中的作用。
在这里，我们证明了抗雄激素分子氟他胺能够拮抗 DHEA 对 RACK1 和 GRβ 表达以及细胞因子产生的刺激作用。在 THP-1 细胞和人外周血单核细胞（PBMC）中，氟他胺阻断了 DHEA 的作用，表明 AR 在这些作用中起作用。由于 DHEA 不被认为是直接的 AR 激动剂，我们研究了 DHEA 在 THP-1 细胞中的代谢。我们评估了睾酮、DHT 和雄烯二酮诱导 RACK1 表达和细胞因子产生的能力。与 DHEA 类似，用这些选定的雄激素处理后，观察到 RACK1 表达增加以及 LPS 诱导的 IL-8 和 TNF-α 产生增加。最后，用 siRNA 沉默 AR 完全阻止了 DHEA 诱导的 RACK1 mRNA 表达，支持了 AR 参与 DHEA 作用的观点。
我们证明了 DHEA 向活性雄激素的转化，这些雄激素通过 AR 起作用，是 DHEA 对 RACK1 表达和单核细胞激活作用的关键机制。这一数据支持了在免疫调节控制中存在复杂激素平衡的观点，这可以在免疫衰老和内分泌衰老的背景下进一步研究。
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