Development of Refractoriness of HO‐1 Induction to a Second Treatment with UVA Radiation and the Involvement of Nrf2 in Human Skin Fibroblasts
Development of Refractoriness of HO‐1 Induction to a Second Treatment with UVA Radiation and the Involvement of Nrf2 in Human Skin Fibroblasts
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DOI：
10.1111/php.12343
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发表时间：
2014-11
影响因子：
3.3
通讯作者：
J. Zhong;C. Raval;M. Nisar;Chunxiang Bian;Jin Zhang;Li Yang-;R. Tyrrell
中科院分区：
文献类型：
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作者：
J. Zhong;C. Raval;M. Nisar;Chunxiang Bian;Jin Zhang;Li Yang-;R. Tyrrell
培养的人皮肤成纤维细胞（FEK 4）的UVA处理先前已显示在第二剂量的UVA辐射后减少血红素加氧酶1（HO-1）的转录激活，这是一种称为不应性的现象。这项研究表明，在第二次UVA辐射后，HO-1蛋白的水平也会降低，Nrf 2水平也会降低，并且Nrf 2在细胞核中的积累较少，而Bach 1确实在细胞核中积累。当初始UVA处理之后是第二剂量时，与单次UVA处理相比，细胞活力进一步降低，细胞膜损伤增加。通过siRNA（siNrf 2）靶向敲低Nrf 2导致HO-1蛋白诱导对第二次UVA或血红素处理的额外不应性，并且该处理还通过第二剂量的UVA辐射进一步增强细胞损伤。然而，用Nrf 2转染导致HO-1对第二剂量UVA的不应性降低，并减少了第二剂量UVA辐射的细胞损伤。这些发现与Nrf 2参与HO-1不应性的提议一致，并且可以作为细胞保护因子，对抗重复暴露于中等剂量UVA辐射引起的细胞损伤。我们认为Nrf 2-HO-1通路的保护作用可能具有临床意义，因为人体皮肤反复暴露于UVA辐射。
UVA treatment of cultured human skin fibroblasts (FEK4) has been shown previously to reduce transcriptional activation of heme oxygenase 1 (HO‐1) following a second dose of UVA radiation, a phenomenon known as refractoriness. This study demonstrates that the levels of HO‐1 protein are also reduced after a second dose of UVA radiation as are Nrf2 levels, and there is less accumulation of Nrf2 in the nucleus where as Bach1 does accumulate in the nucleus. Cell viability is further reduced and cell membrane damage increased as compared with a single UVA treatment when an initial UVA treatment was followed by a second dose. Knockdown of Nrf2 by siRNA (siNrf2) targeting caused additional refractoriness of HO‐1 protein induction to a second UVA or heme treatment and this treatment also further enhanced cell damage by a second dose of UVA radiation. However, transfection with Nrf2 caused less refractoriness of HO‐1 to a second dose of UVA and reduced cell damage by a second dose of UVA radiation. These findings are consistent with the proposal that Nrf2 is involved in HO‐1 refractoriness and could serve as a cytoprotective factor against cell damage caused by repeated exposure to moderate doses of UVA radiation. We propose that protection by the Nrf2‐HO‐1 pathway protection may have clinical relevance since human skin is exposed repeatedly to UVA radiation.