PIAS3调控STAT3/NF-kB和p53信号通路在银屑病发生发展中的作用

Psoriasis is an autoimmune and inflammatory skin disorder, which is characterized by the abnormal inflammation and keratinocyte proliferation, there is still a lack of effective treatment methods. Protein inhibitor of activated STAT3 (PIAS3) can regulate activity and function of several factors including STAT3, NF-kB and p53. STAT3 and NF-kB have been described as crucial players in the pathogenesis of psoriasis, and p53 has regulated cells growth. The relationship between PIAS3 and psoriasis has never been reported before. In our previous studies, we found the expression level of PIAS3 was significantly decreased while that of STAT3 was increased in psoriatic skin lesions, so we speculated that this may be a new mechanism for the occurrence of psoriasis. To confirm our hypothesis, we used bioinformatics analysis and immunohistochemical analysis of clinical psoriatic skin lesions and normal skin specimens to detect the expression level of PIAS3; investigated the effects of PIAS3 on cell proliferation, apoptosis, inflammatory factors and downstream pathways in cells, and the effect of PIAS3 in the therapeutics of psoriasis mouse models. This study will clarify the molecular mechanism of psoriasis from a new perspective and provide a new target for the prevention and treatment of psoriasis.

银屑病是免疫介导的炎症性皮肤病，典型特征为异常免疫反应和角质形成细胞过度增生，尚无有效防治方法。活化型STAT3蛋白抑制因子PIAS3对STAT3、NF-kB和p53的表达与功能有调控作用。研究显示STAT3、NF-kB在炎症和银屑病的发生发展中起重要作用，p53参与细胞增殖调控。关于PIAS3与银屑病发生发展的关系，迄今国内外尚无相关报道。我们前期研究发现银屑病皮损中PIAS3表达量显著下降，而STAT3表达明显上调，推测PIAS3表达异常可能是银屑病发病机制之一。本项目将通过生物信息学分析和检测银屑病临床组织标本PIAS3的表达特点；细胞实验观察PIAS3对角质形成细胞增殖、凋亡、炎症因子表达和下游通路的影响；银屑病样小鼠模型动物实验观察PIAS3对银屑病发生发展的影响，从新的视角探讨银屑病发生的分子机制，为银屑病药物研发提供新靶点。

银屑病是免疫介导的炎症性皮肤病，典型特征为异常免疫反应和角质形成细胞过度增生，尚无有效防治方法。活化型STAT3蛋白抑制因子PIAS3对STAT3、NF-kB和p53的表达与功能有调控作用。研究显示STAT3、NF-kB在炎症和银屑病的发生发展中起重要作用，p53参与细胞增殖调控。关于PIAS3与银屑病发生发展的关系，迄今国内外尚无相关报道。我们前期研究发现银屑病皮损中PIAS3表达量显著下降，而STAT3表达明显上调，推测PIAS3 表达异常可能是银屑病发病机制之一。本项目明确PIAS3在临床银屑病皮损中处于低表达，以及PIAS3基因过表达对人角质形成细胞增殖有抑制作用，可促进细胞发生凋亡，明显促进除p53之外其他因子TNF-α，IL-6，IL-8和K17的mRNA表达水平。阐明PIAS3可能通过调控STAT3和NF-κB启动子活性而参与银屑病分子调控机制。PIAS3过表达对银屑病样小鼠模型，可抑制银屑病样皮损炎症因子（TNF-α、IL-6、IL-8、K17）的表达，而增加p53表达。从新的视角探讨银屑病发生的分子机制，为银屑病药物研发提供新靶点。