發(fā)布時間：2018-03-17 02:26

  本文選題：白介素17A　切入點：白介素33　出處：《華東師范大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：皮膚是人體抵御外界環(huán)境刺激的第一道防線,具有保護機體的作用。當(dāng)皮膚受到創(chuàng)傷時,傷口部位容易被微生物感染并引發(fā)炎癥,影響傷口修復(fù),嚴重的甚至?xí)䦟?dǎo)致傷口潰爛或周邊組織壞死。因此對傷口愈合及微生物感染調(diào)控機制的研究迫在眉睫。我們的前期研究發(fā)現(xiàn)白介素17A(IL-17A),能夠誘導(dǎo)角質(zhì)形成細胞中REG3A的表達,進而抑制分化基因來增強角質(zhì)形成細胞的增殖能力,促進傷口愈合。但是對于IL-17A調(diào)節(jié)REG3A表達的具體分子機制仍未研究清楚。本研究利用IL-17A刺激角質(zhì)形成細胞,通過基因沉默和抑制劑篩選的方式發(fā)現(xiàn)除了需要IL-17RA參與外,其接頭分子Actl和下游信號分子p38 MAPK和P-catenin的激活也是誘導(dǎo)REG3A必需的。此外,在角質(zhì)形成細胞中,IL-17A誘導(dǎo)REG3A的表達是依賴白介素33(IL-33)的。當(dāng)把IL33基因沉默之后,IL-17A不能夠誘導(dǎo)REG3A表達。IL-17A誘導(dǎo)表達的IL-33分泌到細胞外,通過與受體ST2結(jié)合激活JNK-AKT-STAT3信號通路來誘導(dǎo)REG3A的表達。小鼠在體實驗也證明了IL-17A/IL-33/RegⅢ/γ能夠促進皮膚傷口愈合。除了促進受損組織修復(fù),REG3A還能夠作為一種抗菌蛋白,抑制胃腸道中病原微生物的生長。人體的皮膚表面棲息大量的共生菌,與機體形成良好的互利關(guān)系。當(dāng)平衡被打破時,正常菌群則會轉(zhuǎn)變成條件致病菌,引發(fā)各種皮膚的感染性疾病。REG3A在皮膚感染方面的研究至今未有原創(chuàng)性報道。我們發(fā)現(xiàn),REG3A、RegⅢγ和經(jīng)IL-33刺激的角質(zhì)形成細胞裂解液均能夠抑制金黃色葡萄球菌的生長。小鼠在體實驗進一步證明了IL-33誘導(dǎo)RegIIIy的表達進而抑制金黃色葡萄球菌對小鼠皮膚的感染,并且IL-17A參與調(diào)節(jié)金黃色葡萄球菌感染時IL-33和RegⅢγ的表達。綜上所述,我們的研究首次發(fā)現(xiàn)了IL-17A調(diào)節(jié)角質(zhì)形成細胞中IL-33和REG3A的信號機制,并且證明了IL-17A/IL-33/REG3A在促進傷口愈合和抵御金黃色葡萄球菌感染過程中發(fā)揮重要作用。本研究的開展為揭示皮膚創(chuàng)傷后角質(zhì)形成細胞的生理作用提供了新的依據(jù),也為臨床治療皮膚傷口及微生物感染提供新的理論基礎(chǔ)。
[Abstract]:The skin is the body's first line of defense against external environmental stimuli. When the skin is traumatized, the wound is easily infected by microbes and causes inflammation, which affects wound repair. It is urgent to study the regulation mechanism of wound healing and microbial infection. Our previous studies have found that IL-17An can induce the expression of REG3A in keratinocytes. In order to enhance the proliferation ability of keratinocytes and promote wound healing, however, the specific molecular mechanism of IL-17A regulating REG3A expression has not been studied. In this study, IL-17A was used to stimulate keratinocytes. Through gene silencing and inhibitor screening, it was found that the activation of Actl and downstream signaling molecules p38 MAPK and P-catenin were also necessary to induce REG3A in addition to the involvement of IL-17RA. The expression of REG3A in keratinocytes induced by IL-17A is dependent on IL-33). When the IL33 gene is silenced, IL-17A can not induce the expression of REG3A. IL-17A induces the secretion of IL-33 induced by IL-17A into the cells. The expression of REG3A was induced by activating the JNK-AKT-STAT3 signaling pathway by binding to the receptor ST2. The in vivo experiments in mice also demonstrated that IL-17A/IL-33/Reg 鈪，

本文編號：1622768