Roles of sex hormones in the pathogenesis of psoriasis vulgaris and their therapeutic efficacy

本项目的目的是研究性激素对1.角质形成细胞增殖、DNA合成或凋亡的影响2.角质形成细胞自分泌生长因子的产生3.促炎或抗炎细胞因子、趋化因子、或角质形成细胞中的血管生成因子。角质形成细胞中的粘附分子或炎性细胞因子或生长因子的受体5.角质形成细胞中细胞角蛋白的表达。项目1：17β-雌二醇（E2）通过与角质形成细胞表面的GPR 30结合，诱导cAMP信号，增强抗凋亡蛋白Bcl-2的表达，从而抑制氧化应激诱导的细胞凋亡，项目4的结果：（1）E2通过诱导角质形成细胞内cAMP信号，抑制Jak 1，2/Stat 1信号通路，从而抑制1型T细胞趋化因子IP-10的表达。(2)E2抑制角质形成细胞中Sp1和AP-1的转录活性，从而抑制单核细胞/巨噬细胞吸引趋化因子MCP-1的表达。(3)E2抑制角质形成细胞中NF-κB的转录活性，从而抑制RANTES、1型T细胞和单核细胞/巨噬细胞吸引趋化因子的表达。这些结果表明，E2可能抑制银屑病皮损中角质形成细胞的异常增强的凋亡，维持皮肤稳态，并且E2可能抑制1型T细胞或单核细胞/巨噬细胞向银屑病皮损中的浸润，从而减轻炎症。这些结果表明E2对银屑病的治疗效果。项目2、3、5正在进行中。

The aim of this project is to investigate the effects of sex hormones on1.proliferation, DNA synthesis, or apoptosis in keratinocytes2.autocrine growth factor production in keratinocytes3.the production of pro- or anti-inflammatory cytokines, chemokines, or angiogenic factors in keratinocytes4.the expression of cell-adhesion molecules or receptors for inflammatory cytokines or growth factors in keratinocytes5.the expression of cytokeratins in keratinocytes.Our results on project 1:17β-estradiol (E2) binds GPR30 on the surface of keratinocytes and induces cAMP signal which enhances the expression of anti-apoptotic protein, Bcl-2 and thus suppresses apoptosis induced by oxidative stress.Our results on project 4 :(1)E2 suppresses Jak1,2/Stat1 signaling pathway via inducing cAMP signal in keratinocytes and thus suppresses the expression of IP-10, type 1 T cell-attracting chemokine.(2)E2 suppresses transcriptional activities of Sp1 and AP-1 in keratinocytes and thus suppresses the expression of MCP-1, monocyte/macrophage-attracting chemokine.(3)E2 suppresses transcriptional activity of NF-κB in keratinocytes and thus suppresses the expression of RANTES, type 1 T cell- and monocyte/macrophage-attracting chemokine.These results suggest that E2 may suppress abnormally enhanced apoptosis of keratinocytes in psoriatic lesions and maintain skin homeostasis and that E2 may suppress the infiltration of type 1 T cells or monocyte/macrophages into psoriatic skin lesions and thus attenuate inflammation. These results indicate therapeutic efficacy of E2 for psoriasis. Projects 2,3,5 are now on-going.