α-Melanocyte-Stimulating Hormone Counteracts the Suppressive Effect of UVB on Nrf2 and Nrf-Dependent Gene Expression in Human Skin
α-Melanocyte-Stimulating Hormone Counteracts the Suppressive Effect of UVB on Nrf2 and Nrf-Dependent Gene Expression in Human Skin
复制标题
DOI：
10.1210/en.2008-1315
复制
发表时间：
2009-07-01
期刊：
影响因子：
4.8
通讯作者：
Boehm, Markus
中科院分区：
文献类型：
--
作者：
Kokot, Agatha;Metze, Dieter;Boehm, Markus
人类皮肤经常暴露在紫外线下，这是最普遍的环境压力源。在这里，我们研究了 Nrf1-3 的表达和调节，这种转录因子在体外、离体和原位人类皮肤细胞中对抗氧化应激至关重要。特别是，我们检查了 α-MSH（一种紫外线诱导肽）是否能够调节 Nrf2 和 Nrf 依赖性基因表达。发现 Nrf1、-2 和 -3 在体外各种皮肤细胞类型中表达。令人惊讶的是，生理剂量（10 mJ/cm(2)）的UVB照射降低了体外和离体皮肤器官培养物中正常角质形成细胞和黑素细胞中Nrf2和Nrf依赖性基因的表达。 α-MSH 单独显着增加角质形成细胞和黑素细胞中的 Nrf2 以及 Nrf 依赖性血红素加氧酶-1、γ-谷氨酰半胱氨酸合成酶和谷胱甘肽-S-转移酶 Pi 基因表达。 α-MSH 的这种作用在生理剂量下发生，是由于转录诱导引起的，由人工 cAMP 诱导剂毛喉素模仿，并被蛋白激酶 A 途径抑制所阻断。 Nrf2 的计算机启动子分析进一步鉴定了激活蛋白 1 和 cAMP 反应元件结合蛋白（通常由 α-MSH 激活的转录因子）的几个假定结合位点。重要的是，α-MSH 不仅在体外正常角质形成细胞和黑素细胞中，而且在皮肤器官培养物中，阻止甚至过度补偿了 UVB 诱导的 Nrf2 和 Nrf 依赖性基因的抑制。这些发现首次表明 α-MSH 对 Nrf2 和 Nrf 依赖性基因的调节。我们的数据还强调了 α-MSH 以及相关黑皮质素肽的细胞保护和抗氧化效应机制的一个新方面。 （内分泌学 150：3197-3206，2009）
Human skin is constantly exposed to UV light, the most ubiquitous environmental stressor. Here, we investigated the expression and regulation of Nrf1-3, transcription factors crucially involved in protection against oxidative stress in human skin cells in vitro, ex vivo, and in situ. In particular, we examined whether alpha-MSH, a UV-induced peptide, is capable of modulating Nrf2 and Nrf-dependent gene expression. Nrf1, -2, and -3 were found to be expressed in various cutaneous cell types in vitro. Surprisingly, UVB irradiation at physiological doses (10 mJ/cm(2)) reduced Nrf2 and Nrf-dependent gene expression in normal keratinocytes and melanocytes in vitro as well as ex vivo in skin organ cultures. alpha-MSH alone significantly increased Nrf2 as well as Nrf-dependent heme oxygenase-1, gamma-glutamylcysteine-synthetase, and glutathione-S-transferase Pi gene expression in both keratinocytes and melanocytes. This effect of alpha-MSH occurred at physiological doses and was due to transcriptional induction, mimicked by the artificial cAMP inducer forskolin, and blocked by protein kinase A pathway inhibition. In silico promoter analysis of Nrf2 further identified several putative binding sites for activator protein 1 and cAMP response element-binding protein, transcription factors typically activated by alpha-MSH. Importantly, alpha-MSH prevented or even overcompensated the UVB-induced suppression of Nrf2 and Nrf-dependent genes not only in normal keratinocytes and melanocytes in vitro but also in skin organ cultures. These findings, for the first time, show regulation of Nrf2 and Nrf-dependent genes by alpha-MSH. Our data also highlight a novel facet in the cytoprotective and antioxidative effector mechanisms of alpha-MSH and perhaps of related melanocortin peptides. (Endocrinology 150: 3197-3206, 2009)