Ultraviolet irradiation promotes FOXP3 transcription via p53 in psoriasis
Ultraviolet irradiation promotes FOXP3 transcription via p53 in psoriasis
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DOI：
10.1111/exd.12942
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发表时间：
2016-07
影响因子：
3.6
通讯作者：
Dongmei Zhang;Yanghong Chen;Ling Chen;Riyao Yang;Li Wang;Wenying Liu;Z. Zhai;Zhu Shen
中科院分区：
文献类型：
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作者：
Dongmei Zhang;Yanghong Chen;Ling Chen;Riyao Yang;Li Wang;Wenying Liu;Z. Zhai;Zhu Shen
叉头框P3阳性（FOXP3 +）调节性T细胞（Tcells）的减少导致银屑病中效应T细胞的免疫失衡。先前的研究已经证明，除了其对角质形成细胞和效应T细胞的已知作用之外，紫外线（UV）照射通过上调FOXP3 + T细胞而使银屑病恶化。然而，其机制尚不清楚。免疫组化染色显示，UVB照射后银屑病皮损中FOXP3 + T细胞明显增多（t' = 3.7006，P < 0.01）。另外，FOXP3和p53的表达水平在紫外线照射后也呈现出一致的变化。使用MAPK抑制剂、p53突变细胞系、p53抑制剂和p53 shRNA的实验显示FOXP3水平降低，表明p53是UV诱导的FOXP3转录所必需的。接下来，我们通过信息学工具，双荧光素酶报告基因测定和染色质免疫沉淀（ChIP）测定证明FOXP3上有两个p53结合位点。一个结合位点（−1771至−1583）位于启动子区，与先前报道的乳腺癌细胞中的p53结合区相邻。另一个（+3845至+4042）位于第一内含子内，以前没有报道。我们的研究表明，FOXP3的调节，至少部分，通过结合p53的启动子和内含子区域的几个结合位点后，紫外线照射银屑病。这将有助于进一步阐明FOXP 3转录的调节机制，并为介导紫外线照射对自身免疫性皮肤病影响的机制提供新的见解。
The decrease of forkhead box P3‐positive (FOXP3 + ) regulatory T cells (Tregs) causes an immune imbalance with effector T cells in psoriasis. Previous studies have demonstrated that in addition to its known effects on keratinocytes and effector T cells, ultraviolet (UV) irradiation alleviates psoriasis via the upregulation of FOXP3 + Tregs. However, the mechanism is unclear. Here, we found that FOXP3 + T cells were increased in psoriatic lesions after UVB irradiation (t' = 3.7006, P < 0.01), as determined by immunohistochemical staining. In addition, the levels of FOXP3 and p53, one of the downstream targets of UV irradiation, showed accordant changes after UV irradiation. Experiments that used a MAPK inhibitor, p53 mutant cell lines, p53 inhibitor and p53 shRNA showed a decrease in FOXP3 levels, suggesting that p53 is required for UV‐induced FOXP3 transcription. Next, we demonstrated that there are two binding sites for p53 on FOXP3 by informatics tools, a dual‐luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. One binding site (−1771 to −1583) is located at the promoter region and is adjacent to a previously reported p53‐binding region in breast cancer cells. The other (+3845 to +4042) is located within the first intron and has not been previously reported. Our study demonstrated that FOXP3 is regulated, at least in part, by the binding of p53 to several binding sites in the promoter and intron regions following UV irradiation in psoriasis. It will be helpful to further clarify the regulatory mechanism of FOXP3 transcription and to provide new insights into the mechanisms that mediate the effects of UV irradiation in autoimmune skin disorders.