Attenuation of UVB-induced sunburn reaction and oxidative DNA damage with no alterations in UVB-induced skin carcinogenesis in nrf2 gene-deficient mice
Attenuation of UVB-induced sunburn reaction and oxidative DNA damage with no alterations in UVB-induced skin carcinogenesis in nrf2 gene-deficient mice
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DOI：
10.1038/sj.jid.5701245
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发表时间：
2008-07-01
影响因子：
6.5
通讯作者：
Otsuka, Fujio
中科院分区：
文献类型：
--
作者：
Kawachi, Yasuhiro;Xu, Xuezhu;Otsuka, Fujio
紫外线辐射是皮肤老化和癌症发病机制中的重要环境因素。紫外线辐射的许多有害影响与活性氧的产生有关。细胞抗氧化剂可防止紫外线引起的光老化和皮肤疾病的发生并降低其严重程度。转录因子Nrf 2（NF-E2相关因子2）及其负调节蛋白Keap 1（Kelch-like-ECH相关蛋白1）是细胞抗氧化反应的中心调节因子。我们使用nrf 2基因敲除小鼠来研究Nrf 2-Keap 1系统在保护皮肤免受UVB照射的有害影响中的作用。UVB单次照射可诱导nrf 2基因敲除小鼠产生更强、更持久的晒伤反应。UVB照射后的组织学变化，包括表皮坏死、真皮水肿、炎性细胞浸润、晒伤细胞形成、TUNEL阳性凋亡细胞形成和氧化DNA产物如8-羟基-2 '-脱氧鸟苷的积累，在nrf 2基因敲除小鼠中更为突出。这些发现表明，Nrf 2-Keap 1通路在保护皮肤免受急性UVB反应，包括皮肤细胞凋亡和氧化损伤中起着重要作用。然而，暴露于慢性UVB照射的nrf 2-null和野生型小鼠之间的皮肤致癌作用没有显着差异，这表明促进和预防光致癌作用的因素之间存在复杂而微妙的平衡。
UV radiation is an important environmental factor in the pathogenesis of skin aging and cancer. Many harmful effects of UV radiation are associated with generation of reactive oxygen species. Cellular antioxidants prevent the occurrence and reduce the severity of UV-induced photoaging and diseases of the skin. The transcription factor Nrf2 (NF-E2-related factor 2) and its negative regulator protein, Keap1 (Kelch-like-ECH-associated protein 1), are central regulators of cellular antioxidant responses. We used nrf2-null mice to investigate the roles of the Nrf2-Keap1 system in protection of skin from harmful effects of UVB irradiation. A single irradiation with UVB induced stronger and longer lasting sunburn reaction in nrf2-null mice. Histological changes, including epidermal necrosis, dermal edema, inflammatory cell infiltration, sunburn cell formation, TUNEL-positive apoptotic cell formation, and accumulation of oxidative DNA products such as 8-hydroxy-2'- deoxyguanosine after UVB irradiation, were more prominent in nrf2-null mice. These findings indicate that the Nrf2-Keap1 pathway plays an important role in protection of the skin against acute UVB reactions, including cutaneous cell apoptosis and oxidative damage. However, there were no significant differences in skin carcinogenesis between nrf2-null and wild-type mice exposed to chronic UVB irradiation, suggesting that there is a complex and subtle balance between factors promoting and preventing photocarcinogenesis.