Experimental and Translational Respiratory Medicine Group, Level 2 East, Hunter Medical Research Institute, School of Medicine and Public Health, Faculty of Health, University of Newcastle, Callaghan, NSW, 2308, Australia.
Priority Research Centre GrowUpWell, The University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.
BMC Pulm Med. 2019 Feb 7;19(1):31. doi: 10.1186/s12890-019-0786-x.
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.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）先前已被证明通过上调 E3 泛素连接酶 MID1 并随后使蛋白磷酸酶 2A（PP2A）失活，在过敏性气道疾病和 COPD 中发挥促炎作用。
从 2013 年 1 月至 2014 年 2 月在中国吉林大学第二附属医院就诊的 8 名特发性肺纤维化（IPF）患者中获取活检组织，并从切除的肺癌患者中获得对照样本。测量活检组织中的 TRAIL、MID1 蛋白和 PP2A 活性以及患者的肺功能。给予野生型和 TRAIL 缺陷型 Tnfsf10 BALB/c 小鼠博来霉素以诱导纤维化，并对部分组用 FTY720 类似物 AAL(s)处理以激活 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 患者血清 TRAIL 和活检组织中 MID1 蛋白水平升高。MID1 水平呈负相关，而 PP2A 活性水平与 DLco 相关。Tnfsf10 和用 PP2A 激活剂 AAL(s)处理的小鼠在很大程度上免受博来霉素诱导的肺功能下降和纤维化变化的影响。在体外向小鼠成纤维细胞中添加重组 TRAIL 会增加胶原蛋白的产生，而用 AAL(s)激活 PP2A 则可逆转这一过程。
TRAIL 通过 MID1 信号传导使 PP2A 失活并促进纤维化，导致相应的肺功能下降。这可能为 IPF 提供新的治疗靶点。
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