Nrf2 Promotes Keratinocyte Proliferation in Psoriasis through Up-Regulation of Keratin 6, Keratin 16, and Keratin 17
Nrf2 Promotes Keratinocyte Proliferation in Psoriasis through Up-Regulation of Keratin 6, Keratin 16, and Keratin 17
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Nrf2 通过上调角蛋白 6、角蛋白 16 和角蛋白 17 促进银屑病角质形成细胞增殖
DOI：
10.1016/j.jid.2017.05.015
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发表时间：
2017-10-01
影响因子：
6.5
通讯作者：
Wang, Gang
中科院分区：
文献类型：
--
作者：
Yang, Luting;Fan, Xueli;Wang, Gang
银屑病是一种以表皮角化细胞过度增殖为特征的慢性炎症性皮肤病。尽管过度增殖相关的角蛋白K6、K16和K17被认为是银屑病的标志，但这些角蛋白过度表达的分子基础仍不清楚。Nrf 2调节细胞增殖。因此，我们研究了Nrf 2是否通过促进银屑病中K6、K16和K17的表达来调节角质形成细胞增殖。我们最初发现银屑病表皮表现出Nrf 2的表达升高。此外，Nrf 2通过与位于这些基因启动子中的ARE结构域结合，促进HaCaT细胞和原代人角质形成细胞中K6、K16和K17的表达。此外，在用IL-17或IL-22刺激后，Nrf 2易位到细胞核并启动靶向角蛋白的表达。在咪喹莫特诱导的银屑病样皮炎小鼠中，局部应用Nrf 2小干扰RNA减轻了表皮增生，降低了这些角蛋白的表达。更重要的是，Nrf 2通过上调K6、K16或K17促进人角质形成细胞的增殖。这些数据表明，炎症细胞因子促进银屑病表皮Nrf 2核转位，导致K6，K16和K17表达升高，从而促进角质形成细胞增殖，并有助于银屑病的发病机制。
Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation of epidermis. Although hyperproliferation-associated keratins K6, K16, and K17 are considered to be the hallmarks of psoriasis, the molecular basis underlying the overexpression of these keratins remains unclear. Nrf2 regulates cell proliferation. Therefore, we investigated whether Nrf2 regulates keratinocyte proliferation via promoting expression of K6, K16, and K17 in psoriasis. We initially found that psoriatic epidermis exhibited elevated expression of Nrf2. Furthermore, Nrf2 promoted expression of K6, K16, and K17 in both HaCaT cells and primary human keratinocytes by binding to the ARE domains located in the promoter of these genes. Additionally, upon stimulation with IL-17 or IL-22, Nrf2 translocated to the nucleus and initiated expression of targeted keratins. In mice of imiquimod-induced psoriasis-like dermatitis, topical application of Nrf2 small interfering RNA alleviated the epidermal hyperplasia with reduced expression of these keratins. More importantly, Nrf2 promoted the proliferation of human keratinocytes through up-regulation of K6, K16, or K17. These data suggested that inflammatory cytokines promoted Nrf2 nuclear translocation in psoriatic epidermis, which led to elevated expression of K6, K16, and K17, thus promoting keratinocyte proliferation and contributing to the pathogenesis of psoriasis.