High mobility group box 1 induced human lung myofibroblasts differentiation and enhanced migration by activation of MMP-9

Chen Chen Lee, Chien Neng Wang, Yueh Lun Lee, Yi Ru Tsai, Jau Jin Liu, Chuenmao Yang

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere0116393
JournalPLoS One
Volume10
Issue number2
DOIs
Publication statusPublished - Feb 18 2015
Externally publishedYes

Fingerprint

gelatinase B
Myofibroblasts
Matrix Metalloproteinase 9
mitogen-activated protein kinase
Chemical activation
lungs
fibroblasts
Fibroblasts
Lung
phosphotransferases (kinases)
Phosphotransferases
p38 Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases
cell movement
Airway Remodeling
mitogen-activated protein kinase kinase
JNK Mitogen-Activated Protein Kinases
nuclear proteins
protein binding
Bromodeoxyuridine

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

High mobility group box 1 induced human lung myofibroblasts differentiation and enhanced migration by activation of MMP-9. / Lee, Chen Chen; Wang, Chien Neng; Lee, Yueh Lun; Tsai, Yi Ru; Liu, Jau Jin; Yang, Chuenmao.

In: PLoS One, Vol. 10, No. 2, e0116393, 18.02.2015.

Research output: Contribution to journalArticle

Lee, Chen Chen ; Wang, Chien Neng ; Lee, Yueh Lun ; Tsai, Yi Ru ; Liu, Jau Jin ; Yang, Chuenmao. / High mobility group box 1 induced human lung myofibroblasts differentiation and enhanced migration by activation of MMP-9. In: PLoS One. 2015 ; Vol. 10, No. 2.
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