High mobility group box 1 induced human lung myofibroblasts differentiation and enhanced migration by activation of MMP-9.
High mobility group box 1 induced human lung myofibroblasts differentiation and enhanced migration by activation of MMP-9.
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DOI：
10.1371/journal.pone.0116393
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Liu JJ
中科院分区：
文献类型：
--
作者：
Lee CC;Wang CN;Lee YL;Tsai YR;Liu JJ
高迁移率族蛋白1（HMGB 1）是一种与DNA结合的核蛋白，影响染色质的调控和转录。HMGB 1也是一种细胞因子，可以激活参与炎症的单核细胞和中性粒细胞。在这项研究中，我们研究了HMGB 1对细胞活化的作用，使用人成纤维细胞系WI-38。MTT法和BrdU掺入法分别检测1、10和100 ng/mL的HMGB 1对WI-38细胞作用24 h后，未见明显的细胞毒性和细胞增殖。然而，我们发现用10和100 ng/mL的HMGB 1处理诱导肺成纤维细胞分化为肌成纤维细胞，并且肌成纤维细胞通过激活基质金属蛋白酶（MMP）-9活化而显示出更高的迁移能力。为了阐明HMGB 1诱导细胞迁移的机制，我们检测了HMGB 1诱导的丝裂原活化蛋白激酶（MAPK），包括细胞外信号相关激酶（ERK）、c-Jun N末端激酶（JNK）和p38丝裂原活化蛋白激酶（p38）磷酸化，以及核因子（NF）-κB核转位。我们使用特异性蛋白激酶抑制剂和shRNAs，观察到ERK、JNK、p38和NF-κB的抑制均抑制了HMGB 1诱导的WI-38细胞分化、迁移和MMP-9的活化。此外，通过shRNA敲低HMGB 1而非TLR 2和TLR 4可减弱HMGB 1诱导的肌成纤维细胞分化和迁移。结论：HMGB 1通过诱导MMP-9活化、RAGE-MAPK和NF-κB相互作用信号通路，诱导肺成纤维细胞向肌成纤维细胞分化，增强细胞迁移。靶向HMGB 1可能是缓解慢性气道炎症性疾病中气道重塑的潜在治疗方法。
High mobility group box 1 (HMGB1) is a nuclear protein that involves the binding with DNA and influences chromatin regulation and transcription. HMGB1 is also a cytokine that can activate monocytes and neutrophils involved in inflammation. In this study, we investigated the role of HMGB1 on cellular activation using human fibroblast cell line WI-38. After treatment with 1, 10, and 100 ng/mL of HMGB1 for 24 h, we did not find obviously cytotoxicity and cellular proliferation of WI-38 cells by MTT and BrdU incorporation assay, respectively. However, we found that treatment with 10 and 100 ng/mL of HMGB1 induced the differentiation of lung fibroblasts into myofibroblasts and myofibroblasts showed higher migration ability through activation of matrix metalloproteinase (MMP)-9 activation. To delineate the mechanism underlying HMGB1-induced cellular migration, we examined HMGB1-induced mitogen activated protein kinases (MAPKs), including extracellular signal related kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen activated protein kinase (p38) phosphorylation, as well as nuclear factor (NF)-κB nuclear translocation. Using specific inhibitors and shRNAs of protein kinases, we observed that repression of ERK, JNK, p38, and NF-κB all inhibited HMGB1-induced cellular differentiation, migration and MMP-9 activation in WI-38 cells. In addition, knocking down of RAGE but not TLR2 and TLR4 by shRNAs attenuated HMGB1-induced myofibroblast differentiation and migration. In conclusion, our study demonstrated that HMGB1 induced lung fibroblasts’ differentiation into myofibroblasts and enhanced cell migration through induction of MMP-9 activation and the RAGE-MAPK and NF-κB interaction signaling pathways. Targeting HMGB1 might be a potential therapeutic approach for alleviation of airway remodeling seen in chronic airway inflammatory diseases.
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DOI：
10.1165/rcmb.2007-0330oc
发表时间：
2008-10-01
影响因子：
6.4
作者：
Hamada, Naoki;Maeyama, Takashige;Nakanishi, Yoichi
通讯作者：
Nakanishi, Yoichi
影响因子：
6.1
作者：
Lee, Chen-Chen;Wang, Chien-Neng;Lai, Yu-Ting
通讯作者：
Lai, Yu-Ting
影响因子：
6.1
作者：
Lee, Chen-Chen;Kang, Jaw-Jou;Cheng, Yu-Wen
通讯作者：
Cheng, Yu-Wen
影响因子：
5.5
作者：
Park, JS;Arcaroli, J;Abraham, E
通讯作者：
Abraham, E
影响因子：
3.2
作者：
Lee, Chen-Chen;Huang, Shih-Hsuan;Kang, Jaw-Jou
通讯作者：
Kang, Jaw-Jou