白介素-17A抑制GSK3β介导的细胞自噬调节机制及其在肺纤维化中的应用
发布时间：2018-07-20 21:51
【摘要】：肺纤维化是各种内、外致病原引起慢性肺疾病的共同后果,以肺组织炎症和纤维化为共同病理特征,严重威胁人类健康和生命。获得性免疫反应特别是Thl、Th2反应的极化方向是肺纤维化发生和发展的关键。此外,Thl7型免疫反应亦参与了肺纤维化的调节。本实验室的前期工作发现免疫细胞因子IL-17A参与了多种急性以及慢性肺纤维化的发生发展,阻断IL-17A的活性,可以抑制由博来霉素或Si02所诱导的肺纤维化,其主要的作用机理是促进炎症的转归以及激活自噬的发生。自噬是一种细胞代谢过程,主要是指溶酶体对细胞自身结构(如细胞器、核酸或蛋白质等生物大分子)进行降解,为细胞的重建、再生和修复提供原料,实现细胞的再循环和再利用。激活自噬的发生可以促进胶原的降解,从而改善肺部急性或慢性纤维化的病变情况。尽管IL-17A可以通过抑制自噬而促进肺纤维化,但是IL-17A调节自活性噬的明确信号通路及分子机制并未被得到详细的阐明。在本文中我们发现了,IL-17A可以通过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,从而促进Bcl-2与Beclin-1的结合,抑制自噬的活化。此外,我们还发现IL-17A可以通过PI3K(I型)-GSK3β信号传导通路调节Bcl-2的Ser70位磷酸化。当IL-17A激活PI3K(Ⅰ型)时,P13K(Ⅰ型)可以磷酸化GSK3β Ser9位从而抑制GSK3β的活性,继而抑制GSK3p与Bcl-2的相互结合,最终抑制Bcl-2的泛素化降解。当GSK3p与Bcl-2的相互结合时,GSK3p可以直接使Bcl-2的Ser70位磷酸化,从而促进Bcl-2的泛素化聚集,加速Bcl-2的降解。因此,IL-17A抑制Bcl-2的降解继而抑制自噬的活化导致了肺纤维化的加剧。以上的结果高度提示,由IL-17A调节的PI3K(Ⅰ型)-GSK3β-Bcl-2信号通路调节了自噬的活化,从分子机制上阐明了IL-17A促进肺纤维化发生的致病机制。 自噬-溶酶体降解途径是肺纤维化疾病中胶原的主要降解途径,自噬的失能即可引起胶原的过度堆积。本文中的研究表明,GSK3β抑制剂SB216763可以通过恢复自噬的活性,改善由博来霉素诱导的急性肺纤维化。体内及体外的实验结果表明,SB216763可以促进多种自噬相关蛋白的表达；此外,SB216763可以抑制Bcl-2与Beclin-1的结合,直接激活自噬核心复合物；最后,SB216763通过促进Bcl-2与GSK3p的结合,从而抑制了Bcl-2与Beclin-1的结合。这一结果提示了,使用GSK3β抑制剂SB216763可以通过适度的活化自噬,最终改善由博来霉素诱导的急性肺纤维化,为治疗肺纤维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，
本文编号：2134903
[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，
本文编号：2134903
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