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首页> 外文期刊>BMC Pulmonary Medicine >TRAIL signals through the ubiquitin ligase MID1 to promote pulmonary fibrosis
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TRAIL signals through the ubiquitin ligase MID1 to promote pulmonary fibrosis

机译：TRAIL信号通过泛素连接酶MID1促进肺纤维化

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Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has previously been demonstrated to play a pro-inflammatory role in allergic airways disease and COPD through the upregulation of the E3 ubiquitin ligase MID1 and the subsequent deactivation of protein phosphatase 2A (PP2A). Biopsies were taken from eight IPF patients presenting to the Second Affiliated Hospital of Jilin University, China between January 2013 and February 2014 with control samples obtained from resected lung cancers. Serum TRAIL, MID1 protein and PP2A activity in biopsies, and patients’ lung function were measured. Wild type and TRAIL deficient Tnfsf10?/? BALB/c mice were administered bleomycin to induce fibrosis and some groups were treated with the FTY720 analogue AAL(s) to activate PP2A. Mouse fibroblasts were treated with recombinant TRAIL and fibrotic responses were assessed. TRAIL in serum and MID1 protein levels in biopsies from IPF patients were increased compared to controls. MID1 levels were inversely associated while PP2A activity levels correlated with DLco. Tnfsf10?/? and mice treated with the PP2A activator AAL(s) were largely protected against bleomycin-induced reductions in lung function and fibrotic changes. Addition of recombinant TRAIL to mouse fibroblasts in-vitro increased collagen production which was reversed by PP2A activation with AAL(s). TRAIL signalling through MID1 deactivates PP2A and promotes fibrosis with corresponding lung?function decline. This may provide novel therapeutic targets for IPF.
机译：先前已证明，肿瘤坏死因子相关的凋亡诱导配体（TRAIL）通过上调E3泛素连接酶MID1和随后的蛋白磷酸酶2A（PP2A）失活而在变应性气道疾病和COPD中起促炎作用。在2013年1月至2014年2月期间，从八名IPF患者的活检样本中抽取了吉林大学第二附属医院的患者，并从切除的肺癌中获得了对照样本。测量活检中的血清TRAIL，MID1蛋白和PP2A活性以及患者的肺功能。野生型和TRAIL缺失的Tnfsf10？/？给BALB / c小鼠施用博来霉素诱导纤维化，并用FTY720类似物AAL治疗某些组以激活PP2A。用重组TRAIL处理小鼠成纤维细胞，并评估纤维化反应。与对照组相比，IPF患者活检的血清中TRAIL和MID1蛋白水平增加。 MID1水平呈负相关，而PP2A活性水平与DLco相关。 Tnfsf10？/？使用PP2A激活剂AAL治疗的小鼠和小鼠在很大程度上受到博来霉素诱导的肺功能下降和纤维化改变的保护。体外向小鼠成纤维细胞中添加重组TRAIL可增加胶原蛋白的产生，而胶原蛋白的产生可通过用AAL激活PP2A来逆转。通过MID1发出的TRAIL信号使PP2A失活并促进纤维化，相应的肺功能下降。这可能为IPF提供新的治疗靶标。

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