Steroid synthesis by primary human keratinocytes; implications for skin disease
Steroid synthesis by primary human keratinocytes; implications for skin disease
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DOI：
10.1016/j.bbrc.2010.11.059
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发表时间：
2011-01-07
影响因子：
3.1
通讯作者：
Philpott, Michael P.
中科院分区：
文献类型：
--
作者：
Hannen, Rosalind F.;Michael, Anthony E.;Philpott, Michael P.
以皮质醇为基础的治疗是治疗牛皮癣和特应性皮炎等皮肤病最有效的抗炎治疗方法之一。先前的研究已经调查了角质形成细胞的类固醇生成能力，尽管没有人证明这些皮肤细胞（占表皮的90%）能够合成皮质醇。在这里，我们证明了原代人角质形成细胞（PHK）表达皮质醇类固醇形成所需的所有元素，并通过每种中间类固醇代谢孕烯醇酮到皮质醇。我们发现正常表皮和培养的PHK表达皮质醇合成所需的每一种酶（CYP11A1、CYP17A1、3 β HSD1、CYP21和CYP11B1）。这些酶被证明对皮质醇合成具有代谢活性，因为放射转化试验追踪了[7-H-3]-孕烯醇酮在培养的PHK中通过每种类固醇中间体代谢为[7-H-3]-皮质醇。Trilostane（一种3 β SD1抑制剂）和酮康唑（一种CYP17A1抑制剂）阻断孕烯醇酮和孕酮的代谢。最后，我们发现正常皮肤表达两种胆固醇转运蛋白，类固醇生成急性调节蛋白（StAR），被认为是类固醇合成的速率决定蛋白，以及转移性淋巴结64 (MLN64)，其功能与类固醇生成过程中的胆固醇转运有关。StAR和MLN64在牛皮癣和特应性皮炎两种皮肤病中表达异常，这两种皮肤病通常用皮质醇治疗，提示这些患者表皮类固醇合成失调。总的来说，这些数据表明PHK能够合成肾上腺外皮质醇，这可能是皮肤生物学的基本途径，与牛皮癣和特应性皮炎有关。(C) 2010爱思唯尔公司版权所有。
Cortisol-based therapy is one of the most potent anti-inflammatory treatments available for skin conditions including psoriasis and atopic dermatitis. Previous studies have investigated the steroidogenic capabilities of keratinocytes, though none have demonstrated that these skin cells, which form up to 90% of the epidermis are able to synthesise cortisol. Here we demonstrate that primary human keratinocytes (PHK) express all the elements required for cortisol steroidogenesis and metabolise pregnenolone through each intermediate steroid to cortisol. We show that normal epidermis and cultured PHK express each of the enzymes (CYP11A1, CYP17A1, 3 beta HSD1, CYP21 and CYP11B1) that are required for cortisol synthesis. These enzymes were shown to be metabolically active for cortisol synthesis since radiometric conversion assays traced the metabolism of [7-H-3]-pregnenolone through each steroid intermediate to [7-H-3]-cortisol in cultured PHK. Trilostane (a 3 beta SD1 inhibitor) and ketoconazole (a CYP17A1 inhibitor) blocked the metabolism of both pregnenolone and progesterone. Finally, we show that normal skin expresses two cholesterol transporters, steroidogenic acute regulatory protein (StAR), regarded as the rate-determining protein for steroid synthesis, and metastatic lymph node 64 (MLN64) whose function has been linked to cholesterol transport in steroidogenesis. The expression of StAR and MLN64 was aberrant in two skin disorders, psoriasis and atopic dermatitis, that are commonly treated with cortisol, suggesting dysregulation of epidermal steroid synthesis in these patients. Collectively these data show that PHK are capable of extra-adrenal cortisol synthesis, which could be a fundamental pathway in skin biology with implications in psoriasis and atopic dermatitis. (C) 2010 Elsevier Inc. All rights reserved.