Open AccessHigh Mobility Group Box 1 Induced Human Lung Myofibroblasts Differentiation and Enhanced Migration by Activation of MMP-9
Author(s) -
Lee Chen-Chen,
Chien-Neng Wang,
Yueh-Lun Lee,
Yi-Ru Tsai,
Jau-Jin Liu
Publication year - 2015
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0116393
Subject(s) - hmgb1 , microbiology and biotechnology , kinase , mapk/erk pathway , p38 mitogen activated protein kinases , rage (emotion) , protein kinase a , cell migration , chemistry , myofibroblast , signal transduction , fibroblast , biology , cancer research , cell culture , inflammation , cell , immunology , medicine , biochemistry , fibrosis , neuroscience , genetics
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.