【摘要】：肺纖維化是各種內(nèi)、外致病原引起慢性肺疾病的共同后果,以肺組織炎癥和纖維化為共同病理特征,嚴重威脅人類健康和生命。獲得性免疫反應特別是Thl、Th2反應的極化方向是肺纖維化發(fā)生和發(fā)展的關(guān)鍵。此外,Thl7型免疫反應亦參與了肺纖維化的調(diào)節(jié)。本實驗室的前期工作發(fā)現(xiàn)免疫細胞因子IL-17A參與了多種急性以及慢性肺纖維化的發(fā)生發(fā)展,阻斷IL-17A的活性,可以抑制由博來霉素或Si02所誘導的肺纖維化,其主要的作用機理是促進炎癥的轉(zhuǎn)歸以及激活自噬的發(fā)生。自噬是一種細胞代謝過程,主要是指溶酶體對細胞自身結(jié)構(gòu)(如細胞器、核酸或蛋白質(zhì)等生物大分子)進行降解,為細胞的重建、再生和修復提供原料,實現(xiàn)細胞的再循環(huán)和再利用。激活自噬的發(fā)生可以促進膠原的降解,從而改善肺部急性或慢性纖維化的病變情況。盡管IL-17A可以通過抑制自噬而促進肺纖維化,但是IL-17A調(diào)節(jié)自活性噬的明確信號通路及分子機制并未被得到詳細的闡明。在本文中我們發(fā)現(xiàn)了,IL-17A可以通過降低自噬抑制性蛋白Bcl-2的Ser70位磷酸化,抑制Bcl-2的泛素化降解,從而促進Bcl-2與Beclin-1的結(jié)合,抑制自噬的活化。此外,我們還發(fā)現(xiàn)IL-17A可以通過PI3K(I型)-GSK3β信號傳導通路調(diào)節(jié)Bcl-2的Ser70位磷酸化。當IL-17A激活PI3K(Ⅰ型)時,P13K(Ⅰ型)可以磷酸化GSK3β Ser9位從而抑制GSK3β的活性,繼而抑制GSK3p與Bcl-2的相互結(jié)合,最終抑制Bcl-2的泛素化降解。當GSK3p與Bcl-2的相互結(jié)合時,GSK3p可以直接使Bcl-2的Ser70位磷酸化,從而促進Bcl-2的泛素化聚集,加速Bcl-2的降解。因此,IL-17A抑制Bcl-2的降解繼而抑制自噬的活化導致了肺纖維化的加劇。以上的結(jié)果高度提示,由IL-17A調(diào)節(jié)的PI3K(Ⅰ型)-GSK3β-Bcl-2信號通路調(diào)節(jié)了自噬的活化,從分子機制上闡明了IL-17A促進肺纖維化發(fā)生的致病機制。 自噬-溶酶體降解途徑是肺纖維化疾病中膠原的主要降解途徑,自噬的失能即可引起膠原的過度堆積。本文中的研究表明,GSK3β抑制劑SB216763可以通過恢復自噬的活性,改善由博來霉素誘導的急性肺纖維化。體內(nèi)及體外的實驗結(jié)果表明,SB216763可以促進多種自噬相關(guān)蛋白的表達；此外,SB216763可以抑制Bcl-2與Beclin-1的結(jié)合,直接激活自噬核心復合物；最后,SB216763通過促進Bcl-2與GSK3p的結(jié)合,從而抑制了Bcl-2與Beclin-1的結(jié)合。這一結(jié)果提示了,使用GSK3β抑制劑SB216763可以通過適度的活化自噬,最終改善由博來霉素誘導的急性肺纖維化,為治療肺纖維化疾病提供了新思路。
[Abstract]:Pulmonary fibrosis is a common consequence of chronic lung diseases caused by various internal and external pathogenic agents. Pulmonary inflammation and fibrosis are common pathological features and threaten human health and life seriously. The polarization direction of the acquired immune response, especially ThlP Th2 response, is the key to the occurrence and development of pulmonary fibrosis. In addition, Thl 7 immune response is also involved in the regulation of pulmonary fibrosis. Our previous work has shown that the immune cytokine IL-17A is involved in the occurrence and development of various acute and chronic pulmonary fibrosis, blocking the activity of IL-17A and inhibiting pulmonary fibrosis induced by bleomycin or SiO2. Its main mechanism is to promote the outcome of inflammation and activation of autophagy. Autophagy is a metabolic process in which lysosomes degrade cell structures (such as organelles, nucleic acids or proteins) and provide raw materials for cell reconstruction, regeneration and repair. To realize cell recycling and reuse. Activation of autophagy can promote collagen degradation, thereby improving the pathological changes of acute or chronic pulmonary fibrosis. Although IL-17A can promote pulmonary fibrosis by inhibiting autophagy, the clear signaling pathway and molecular mechanism of IL-17A regulating autophagy have not been elucidated in detail. In this paper, we found that IL-17A can inhibit the degradation of ubiquitin of Bcl-2 by decreasing the phosphorylation of Bcl-2, thus promoting the binding of Bcl-2 to Beclin-1 and inhibiting the activation of autophagy. In addition, we also found that IL-17A can regulate the Ser70-site phosphorylation of Bcl-2 through PI3K (type I) -GSK3 尾 signaling pathway. When IL-17A activates PI3K (type 鈪，

本文編號：2134903