TNF-α-induced NF-κB activation promotes myofibroblast differentiation of LR-MSCs and exacerbates bleomycin-induced pulmonary fibrosis
TNF-α-induced NF-κB activation promotes myofibroblast differentiation of LR-MSCs and exacerbates bleomycin-induced pulmonary fibrosis
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DOI：
10.1002/jcp.26112
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发表时间：
2018-03-01
影响因子：
5.6
通讯作者：
Han, Xiaodong
中科院分区：
文献类型：
--
作者：
Hou, Jiwei;Ma, Tan;Han, Xiaodong
特发性肺纤维化(IPF)是一种原因不明的慢性、进行性、不可逆转的肺部疾病。已有研究表明，肺间充质干细胞(LR-MSCs)和肿瘤坏死因子-α(TNF-α)在肺纤维化的发生发展中起重要作用。然而，LR-MSCs和TNF-α在肺纤维化发病机制中的潜在联系仍不清楚。在本研究中，我们发现促炎细胞因子TNF-α和转录因子核因子-kappaB(NF-kappa B)p65亚单位在博莱霉素诱导的肺纤维化组织中均上调。此外，我们还发现，肿瘤坏死因子-α通过激活核因子-kappaB信号促进LR-MSCs向肌成纤维细胞分化。有趣的是，我们还发现，肿瘤坏死因子-a促进了β-连环蛋白的表达。此外，抑制核因子-kappaB信号通路可以抑制LR-MSCs的肌成纤维细胞分化和博莱霉素诱导的肺纤维化，并伴随β-catenin表达的降低。我们的数据暗示，抑制核因子-kappa B信号通路可能为肺纤维化提供一种治疗策略，这种疾病需要更有效的治疗方法。
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible lung disease of unknown cause. It has been reported that both lung resident mesenchymal stem cells (LR-MSCs) and tumor necrosis factor-alpha (TNF-alpha) play important roles in the development of pulmonary fibrosis. However, the underlying connections between LR-MSCs and TNF-alpha in the pathogenesis of pulmonary fibrosis are still elusive. In this study, we found that the pro-inflammatory cytokine TNF-alpha and the transcription factor nuclear factor kappa B (NF-kappa B) p65 subunit were both upregulated in bleomycin-induced fibrotic lung tissue. In addition, we discovered that TNF-alpha promotes myofibroblast differentiation of LR-MSCs through activating NF-kappa B signaling. Interestingly, we also found that TNF-a promotes the expression of beta-catenin. Moreover, we demonstrated that suppression of the NF-kappa B signaling could attenuate myofibroblast differentiation of LR-MSCs and bleomycin-induced pulmonary fibrosis which were accompanied with decreased expression of beta-catenin. Our data implicates that inhibition of the NF-kappa B signaling pathway may provide a therapeutic strategy for pulmonary fibrosis, a disease that warrants more effective treatment approaches.