氧化苦参碱抑制SERPINB4表达改善银屑病皮肤炎症的机制

银屑病是多基因介导的免疫性疾病。丝氨酸蛋白酶抑制剂SERPINB4高表达反馈增强免疫反应可能是银屑病发病的机制。文献和前期研究显示氧化苦参碱(Oxymatrine，OMT)可有效治疗银屑病，并下调TGF-β1及其调控的SERPINB4表达，阻断下游IL-17/IL-22通路和补体系统的异常活化。但OMT通过阻断TGF-β/SMAD途径抑制银屑病SERPINB4表达的机制尚未阐明。课题组拟构建过/低SERPINB4表达的HaCaT细胞模型、3D表皮模型和咪喹莫特银屑病小鼠模型，在OMT、TGF-β1及TGF-βRI抑制剂LY2157299干预下，明确OMT抑制SERPINB4改善炎症的作用；利用荧光素酶系统阐明OMT抑制SMAD3调控的SERPINB4基因转录激活机制；CoIP结合质谱方法探讨OMT对SERPINB4蛋白互作网络的影响，发掘OMT抑制SERPINB4活性在银屑病治疗中的价值。

Psoriasis is a chronic inflammatory disease that is more likely to relapse. It may be an important mechanism of psoriasis that the abnormal expression of SERPINB4 enhanced inflammatory pathways positive feedback. Literature and recent research have shown that oxymatrine (OMT) can effectively treat psoriasis in clinic trail , and down-regulation of TGF-β1 and SERPINB4 gene was detected. OMT may be blocked the IL-17/IL-22 inflammatory pathway through down-regulated expression of TGF-β1 and SERPINB4, inhibitting the abnormal activation of the complement system. However, the mechanism OMT inhibitting the expression of SERPINB4 in psoriatic has not been fully elucidated by blocking the TGF-β/SMAD pathway. Under the intervention of OMT, TGF-β1 and TGF-βRI inhibitor LY2157299, it is clear that OMT inhibits the expression of SERPINB4 gene and improves inflammation through constructing HaCaT cell model, 3D skin epidermal cell model and imiquimod-induced mouse model of psoriasis by using gene interruption and overexpression. It was clarified that the mechanism of OMT inhibitting expression of SERPINB4 gene which transcriptional activation via SMAD3 protein promoter binding by dual luciferase reporter assay system; the SERPINB4-interacting proteins- TGF-β1 and SMAD3 were further confirmed by protein interaction network screening by immunoprecipitation combined with mass spectrometry under the of OMT, TGF-β1and TGF-βRI inhibitor LY2157299. This study demonstrated that the clinical applications value of OMT by protease inhibition activity of SERPINB4 in psoriasis.