角蛋白17(K17)作為自身抗原銀屑病發(fā)病機(jī)制中的作用研究
[Abstract]:Psoriasis is a common and recurrent chronic inflammatory skin disease, which is a co-mediated autoimmune disorder of Th1/ Th17 cells. Interleukin-17 (IL-17) is a major cytokine secreted by Th17 cells of T-cell subpopulations, and plays an important role in the pathogenesis of psoriasis, which is considered to be a "Key Cytokine in Psoriasis". The IL-17 signal transduction mechanism consists of three pathways: JAK/ STAT, NF-EMAB and MAPK, where JAK/ STAT is closely related to psoriatic keratinocytes (KC). The keratin 17 (K17) is a "psoriasis-related cytokeratin", and has the same sequence of ALEEAN as the Streptococcus M protein, can specifically stimulate the psoriasis T cells, activate and release the inflammatory factors such as the IFN-1 and the like, and the IFN-1 can increase the expression of the K17 through the STAT1 signal path, so that the body can generate the self-immune response to the K17, So as to form a malignant loop, which leads to the pathological changes of the inflammatory reaction and the abnormal proliferation of the KC, and is a key link in the pathogenesis of the psoriasis. The high expression of K17 in psoriatic lesions and its role in stimulating T cell activation are defined as candidate target antigens for the self-reactive T cell identification of psoriasis. Our previous studies have shown that there is a "K17-T cell-derived cytokine loop" in the pathological process of psoriasis, which may be an important basis for the persistence and recurrence of psoriatic lesions. This study first proposed and verified that IL-17 was an important cytokine in the loop, and the effect of IL-17 on the expression of K17 in the epidermal keratinocytes (KC) and the signal to be controlled by IL-17 were observed. To further study the significance of K17 as its own antigen in the pathogenesis of psoriasis, so as to deepen the understanding of the pathogenesis of psoriasis and to provide a new method for the treatment of psoriasis. The main experiment The method and results are as follows:1) DMEM/10% FBS culture is used The cultured HaCaT cells were cultured in a culture group;2) an IL-17 of 10 U/ mL,50 U/ mL,250 U/ mL and 500 U/ mL was applied to the cultured HaCaT cells, respectively, to IFN-1. The treated HaCaT cells were positive controls and did not apply any dry The pre-prepared HaCaT cells are used as the blank control, and the cells are harvested after the culture is cultured for 24 to 72 hours, and the RNA and the RNA are respectively extracted. the protein is used for detecting the expression level of K17;3) the expression level of K17 is determined from the mRNA and the protein level by using real-time fluorescence quantitative RT-PCR, ELISA, Western blot, confocal immunofluorescence and the like, Screening of IL-17-Induced K17 The best concentration of expression, observed for dose-dependent relationship;4) for screening The best concentration of IL-17 was used to treat the cultured HaCaT cells;5) the antibodies against STAT1 and STAT3 and the respective phosphorylated products were incubated with HaCaT cells, ELISA, Western b, And 6) the untreated HaCaT cells are respectively added with a corresponding signal molecule inhibitor, Fludarpine and Piceatanol for 2 hours, and then IL-17 is added for culturing the HaCaT cell, and after 12 to 24 hours, the real-time quantitative RT-PCR, the ELISA, the Western blot and the immunity are used. The effect of the signal molecule inhibitor on the expression of IL-17 on the expression of K17 was observed by light and the like. The results of the study: IL-17 induced the expression of K17 in the in vitro cultured HaCaT cells in a dose-dependent manner. The mechanism of regulation and control of K17 expression was realized by two signal transduction pathways of STAT1 and STAT3. The first time in this study, a new pathway _ IL-17, which regulates the expression of K17, was found to induce the expression of K17, and the main signal transduction mechanism of the expression of IL-17 in the regulation of K17 was confirmed by the STAT1 and STAT3 signaling pathways, and the
"K17-T cell was further improved. l-derived cytokine loop unk> and its significance in the pathogenesis of psoriasis, and the preliminary elucidation of K17 as its own antigen
【學(xué)位授予單位】:第四軍醫(yī)大學(xué)
【學(xué)位級別】:博士
【學(xué)位授予年份】:2010
【分類號】:R758.63
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