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High Mobility Group Box 1 Induced Human Lung Myofibroblasts Differentiation and Enhanced Migration by Activation of MMP-9

By Chen-Chen Lee (586242), Chien-Neng Wang (693141), Yueh-Lun Lee (403469), Yi-Ru Tsai (693142) and Jau-Jin Liu (693143)

Abstract

<div><p>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.</p></div

Topics: Biological Sciences, wi, differentiation, activation, p 38 mitogen, HMGB 1, influences chromatin regulation, jnk, migration, protein kinases, rage, BrdU incorporation assay, Targeting HMGB 1, nf, tlr, dna, mmp, erk, High Mobility Group Box 1 Induced Human Lung Myofibroblasts Differentiation, mtt, mapk, myofibroblast
Year: 2015
DOI identifier: 10.1371/journal.pone.0116393
OAI identifier: oai:figshare.com:article/1322471
Provided by: FigShare
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