Transcriptional regulation of increased CCL2 expression in pulmonary fibrosis involves nuclear factor-κB and activator protein-1
Transcriptional regulation of increased CCL2 expression in pulmonary fibrosis involves nuclear factor-κB and activator protein-1
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DOI：
10.1016/j.biocel.2013.04.003
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发表时间：
2013-07-01
影响因子：
4
通讯作者：
Pang, Linhua
中科院分区：
文献类型：
--
作者：
Deng, Xiaoling;Xu, Mingyan;Pang, Linhua
趋化因子配体2（Chemokine，CC motif）是C-C趋化因子超家族的成员，参与炎症和纤维化过程。对患者和实验动物的研究提供了令人信服的证据，即CCL 2表达增加在纤维增生性肺病的发展中起着重要作用。肺纤维化中上调的CCL 2表达也参与凝血酶在肺损伤期间发挥的强效促纤维化作用。在这里，我们研究了凝血酶在人原代肺成纤维细胞中产生CCL 2的转录机制，并探讨了肺纤维化中CCL 2表达增加的转录机制。凝血酶增加CCL 2 mRNA水平，但不增加mRNA稳定性，表明其在转录上起作用。转录因子与核因子-κ B（NF-κ B）和CCL 2启动子中激活蛋白-1（AP-1）元件的结合增加有助于凝血酶刺激后的转录活性。从患有特发性肺纤维化（IPF）的患者分离的原代人肺成纤维细胞产生比非纤维化肺成纤维细胞显著更高水平的CCL 2。此外，染色质免疫沉淀试验检测到在存在和不存在凝血酶刺激的情况下，NF-κ B p65和AP-1亚基c-Jun与IPF细胞的CCL 2启动子的结合增加。在博来霉素诱导的肺纤维化小鼠模型的肺组织中也观察到p65和c-Jun与CCL 2启动子的显著增加的结合。总的来说，这些发现强烈表明，转录因子与CCL 2启动子中NF-κ B和AP-1元件的结合增加是导致肺纤维化中CCL 2活跃转录表达的原因。(C)2013爱思唯尔有限公司版权所有。
Chemokine (CC motif) ligand-2 (CCL2) is a member of C-C chemokine superfamily that contributes to inflammatory and fibrotic process. Studies in patients and experimental animals provide compelling evidence that increased CCL2 expression plays an important role in the development of fibroproliferative lung disease. The up-regulated CCL2 expression in pulmonary fibrosis is also involved in the potent profibrotic effects that thrombin exerts during lung injury. Here, we investigated the transcriptional mechanism involved in CCL2 production by thrombin in human primary lung fibroblasts and explored the transcriptional mechanism of increased CCL2 expression in pulmonary fibrosis. Thrombin increased CCL2 mRNA levels but not mRNA stability, suggesting it was acting transcriptionally. The increased binding of transcription factors to nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1) elements in the CCL2 promoter contributed to active transcription following thrombin stimulation. Primary human lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis (IPF) produced significantly higher levels of CCL2 than nonfibrotic lung fibroblasts. Furthermore, chromatin immunoprecipitation assays detected increased binding of NF-kappa B p65 and AP-1 subunit c-Jun to the CCL2 promoter of IPF cells both in the presence and absence of thrombin stimulation. The significantly increased binding of p65 and c-Jun to the CCL2 promoter was also observed in the lung tissue of bleomycin-induced pulmonary fibrosis murine model. Collectively, these findings strongly suggest that the increased binding of transcription factors to NF-kappa B and AP-1 elements in the CCL2 promoter is responsible for the active transcription expression of CCL2 in pulmonary fibrosis. (C) 2013 Elsevier Ltd. All rights reserved.