Role of Nrf2 in differentiation and UV reaction of Keratinocytes and melanocytes

紫外线（UV）辐射是参与皮肤老化和癌症的发病机制的最重要的环境因素之一。紫外线辐射的许多有害影响与活性氧的产生有关，细胞抗氧化剂起作用以防止紫外线诱导的光老化和皮肤疾病的发生并降低其严重性。转录因子Nrf 2及其胞质锚蛋白Keap 1是细胞抗氧化反应的中心调节因子。在这项研究中，我们研究了紫外线照射对真皮成纤维细胞中Nrf 2活化的影响。我们发现，UVA照射，而不是UVB，导致核转位和积累的Nrf 2。UVA诱导的Nrf 2的核积累被光敏剂血卟啉增强，表明Nrf 2的激活是由单线态氧介导的。为了评估Nrf 2对UVA辐射的保护作用，我们使用nrf 2和/或keap 1基因敲除小鼠的真皮成纤维细胞检测UVA诱导的细胞凋亡。虽然nrf 2的破坏增加了UVA照射后凋亡细胞的数量，但与野生型对照相比，keap 1的破坏减少了凋亡细胞的数量。因此，这些发现表明Nrf 2-Keap 1通路在保护皮肤免受UVA照射中起着重要作用。

Ultraviolet(UV) radiation is one of the most important environmental factors involved in the pathogenesis of skin aging and cancer. Many harmful effects of UV radiation are associated with the generation of reactive oxygen species, and cellular antioxidants act to prevent the occurrence and reduce the severity of UV-induced photoaging and diseases of the skin. Transcription factor Nrf2 and its cytoplasmic anchor protein Keap1 are central regulators of the cellular antioxidant response. We investigated in this study effects of UV irradiation on the activation of Nrf2 in dermal fibroblasts. We found that UVA irradiation, but not UVB, causes nuclear translocation and accumulation of Nrf2. The nuclear accumulation of Nrf2 induced by UVA was enhanced by the photosensitizer hematoporphyrin, suggesting that Nrf2 activation is mediated by singlet oxygen. To evaluate the protective role of Nrf2 against UVA radiation, we examined UVA-induced apoptosis using dermal fibroblasts derived from nrf2 and/or keap1 gene knockout mice. While disruption of nrf2 increased the number of apoptotic cells following UVA irradiation, disruption of keap1 decreased the apoptotic cell number compared with wild-type controls. These findings thus demonstrate that the Nrf2-Keap1 pathway plays an important role in the protection of the skin against UVA irradiation.