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

紫外线辐射是皮肤老化和癌症发病机制中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，细胞抗氧化剂可以防止紫外线诱导的光老化和皮肤疾病的发生并减轻其严重程度。转录因子Nrf2及其胞质锚定蛋白Keap1是细胞抗氧化反应的中央调节因子。本研究探讨了紫外线照射对真皮成纤维细胞中Nrf2活化的影响。我们发现UVA辐射，而不是UVB辐射，会引起Nrf2的核移位和积聚。光敏剂血卟啉增强了UVA诱导的Nrf2的核聚集，提示Nrf2的激活是由单线态氧介导的。为了评估Nrf2对UVA辐射的保护作用，我们用Nrf2和/或Keap1基因敲除小鼠的真皮成纤维细胞检测了UVA诱导的细胞凋亡。与野生型对照相比，破坏Nrf2基因增加了UVA照射后的凋亡细胞数量，而破坏Keap1基因则减少了凋亡细胞数量。这些结果表明，Nrf2-Keap1通路在皮肤对UVA辐射的保护中起着重要作用。

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.