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Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens.

外周血单核细胞优先激活11-氧化雄激素。

  • 影响因子:5.04
  • DOI:10.1530/EJE-20-1077
  • 作者列表:"Schiffer L","Bossey A","Kempegowda P","Taylor AE","Akerman I","Scheel-Toellner D","Storbeck KH","Arlt W
  • 发表时间:2021-03-01
Abstract

Objective:Androgens are important modulators of immune cell function. The local generation of active androgens from circulating precursors is an important mediator of androgen action in peripheral target cells or tissues. We aimed to characterize the activation of classic and 11-oxygenated androgens in human peripheral blood mononuclear cells (PBMCs). Methods:PBMCs were isolated from healthy male donors and incubated ex vivo with precursors and active androgens of the classic and 11-oxygenated androgen pathways. Steroids were quantified by liquid chromatography-tandem mass spectrometry. The expression of genes encoding steroid-metabolizing enzymes was assessed by quantitative PCR. Results:PBMCs generated eight-fold higher amounts of the active 11-oxygenated androgen 11-ketotestosterone than the classic androgen testosterone from their respective precursors. We identified the enzyme AKR1C3 as the major reductive 17β-hydroxysteroid dehydrogenase in PBMCs responsible for both conversions and found that within the PBMC compartment natural killer cells are the major site of AKRC13 expression and activity. Steroid 5α-reductase type 1 catalyzed the 5α-reduction of classic but not 11-oxygenated androgens in PBMCs. Lag time prior to the separation of cellular components from whole blood increased serum 11-ketotestosterone concentrations in a time-dependent fashion, with significant increases detected from two hours after blood collection. Conclusions:11-Oxygenated androgens are the preferred substrates for androgen activation by AKR1C3 in PBMCs, primarily conveyed by natural killer cell AKR1C3 activity, yielding 11-ketotestosterone the major active androgen in PBMCs. Androgen metabolism by PBMCs can affect the results of serum 11-ketotestosterone measurements, if samples are not separated in a timely fashion. Significance statement:We show that human peripheral blood mononuclear cells (PBMCs) preferentially activate 11-ketotestosterone rather than testosterone when incubated with precursors of both the classic and the adrenal-derived 11-oxygenated androgen biosynthesis pathways. We demonstrate that this activity is catalyzed by the enzyme AKR1C3, which we found to primarily reside in natural killer cells, major contributors to the anti-viral immune defense. This potentially links intracrine 11-oxygenated androgen generation to the previously observed decreased NK cell cytotoxicity and increased infection risk in primary adrenal insufficiency. In addition, we show that PBMCs continue to generate 11-ketotestosterone if the cellular component of whole blood samples is not removed in a timely fashion, which could affect measurements of this active androgen in routine clinical biochemistry.

摘要

目的: 雄激素是免疫细胞功能的重要调节剂。从循环前体局部产生活性雄激素是外周靶细胞或组织中雄激素作用的重要介质。我们旨在表征人类外周血单核细胞 (pbmc) 中经典和11-氧合雄激素的激活。 方法: 从健康男性供体中分离pbmc,并与经典和11-氧合雄激素途径的前体和活性雄激素离体孵育。通过液相色谱-串联质谱法定量类固醇。通过定量PCR评估编码类固醇代谢酶的基因的表达。 结果: pbmc从其各自的前体中产生的活性11-氧化雄激素11-酮睾酮的量是经典雄激素睾酮的8倍。我们鉴定了AKR1C3酶是PBMC中负责两种转化的主要还原性17β-羟基类固醇脱氢酶,并发现PBMC隔室自然杀伤细胞是AKRC13表达和活性的主要位点。类固醇5α-还原酶1型催化pbmc中经典但非11-氧合雄激素的5α-还原。从全血中分离细胞组分之前的滞后时间以时间依赖性方式增加了血清11-酮睾酮浓度,从采血后两小时检测到显著增加。 结论: 11-氧合雄激素是pbmc中AKR1C3激活雄激素的优选底物,主要由自然杀伤细胞AKR1C3活性传递,产生11-酮睾酮,这是pbmc中主要的活性雄激素。如果样品没有及时分离,pbmc的雄激素代谢会影响血清11-酮睾酮测量的结果。 显著性声明: 我们表明,当与经典和肾上腺来源的11-氧合雄激素生物合成途径的前体一起孵育时,人外周血单核细胞 (pbmc) 优先激活11-酮睾酮而不是睾酮。我们证明这种活性是由AKR1C3酶催化的,我们发现它主要存在于自然杀伤细胞中,这是抗病毒免疫防御的主要贡献者。这可能将胞内11-氧合雄激素生成与先前观察到的原发性肾上腺功能不全中NK细胞细胞毒性降低和感染风险增加联系起来。此外,我们表明,如果全血样品的细胞成分没有及时去除,pbmc会继续产生11-酮睾酮,这可能会影响常规临床生物化学中这种活性雄激素的测量。

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