Apurinic/Apyrimidinic Endonuclease 1 Is a Key Modulator of Keratinocyte Inflammatory Responses
Apurinic/Apyrimidinic Endonuclease 1 Is a Key Modulator of Keratinocyte Inflammatory Responses
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DOI：
10.4049/jimmunol.0901856
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发表时间：
2009-11-15
影响因子：
4.4
通讯作者：
Jo, Eun-Kyeong
中科院分区：
文献类型：
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作者：
Lee, Hye-Mi;Yuk, Jae-Min;Jo, Eun-Kyeong
脱嘌呤/脱嘧啶核酸内切酶1/氧化还原因子-1（APEI）在DNA修复和氧化还原信号传导中起作用，使其成为有吸引力的新兴治疗靶点。然而，APE 1在皮肤炎症反应中的作用在很大程度上是未知的。在这项研究中，我们报告说，APE 1是一个关键的上游调节TLR 2依赖性角质形成细胞炎症反应。我们发现APE]在银屑病皮肤表皮层的核表达显著上调。APE 1对低氧诱导因子Ice和NF-κ B的转录激活和核转位是必不可少的，这两种因子在角质形成细胞中的炎症信号传导中都是至关重要的。此外，APE 1在HaCaT细胞和人原代角质形成细胞中TLR 2介导的炎症介质（包括TNF-α、CXCL 8和LL-37）的表达中发挥关键作用。APEI沉默减弱细胞周期蛋白D1/细胞周期蛋白依赖性激酶4的表达和ERK 1/2和Akt的磷酸化，从而影响角质形成细胞增殖。重要的是，TLR 2诱导的活性氧的产生有助于APE 1的核转位和表达，这表明APE 1的亚细胞定位与APE 1本身通过活性氧依赖性信号传导的产生相关的自动调节回路。总之，这些发现确立了APE 1作为人角质形成细胞中TLR 2依赖性炎症反应的主调节因子的作用。免疫学杂志，2009，183：6839-6848.
Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APEI) functions in both DNA repair and redox signaling, making it an attractive emerging therapeutic target. However, the role of APE1 in cutaneous inflammatory responses is largely unknown. In this study, we report that APE1 is a key upstream regulator in TLR2-dependent keratinocyte inflammatory responses. We found that nuclear expression of APE] in epidermal layers was markedly up-regulated in psoriatic skin. APE1 was essential for the transcriptional activation and nuclear translocation of hypoxia-inducible factor-Ice and NF-kappa B, both of which are crucial for inflammatory signaling in keratinocytes. Moreover, APE1 played a crucial role in the expression of TLR2-mediated inflammatory mediators, including TNF-alpha, CXCL8, and LL-37, in HaCaT cells and human primary keratinocytes. Silencing of APEI attenuated cyclin D1/cyclin-dependent kinase 4 expression and phosphorylation of ERK1/2 and Akt, thereby affecting keratinocyte proliferation. Importantly, TLR2-induced generation of reactive oxygen species contributed to the nuclear translocation and expression of APE1, suggesting an autoregulatory circuit in which the subcellular localization of APE1 is associated with the production of APE1 per se through reactive oxygen species-dependent signaling. Taken together, these findings establish a role for APE1 as a master regulator of TLR2-dependent inflammatory responses in human keratinocytes. The Journal of Immunology, 2009, 183: 6839-6848.