High mobility group box 1 activates toll like receptor 4 signaling in hepatic stellate cells

Zhe Zhang, Chenzhao Lin, Lijun Peng, Yangyang Ouyang, Yirong Cao, Jiyao Wang, Scott L. Friedman, Jinsheng Guo

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Aims: The aim of the present study was to investigate the effect of high mobility group box 1 (HMGB1), a damage pattern molecule that signals the presence of necrosis, on TLR4 signaling in hepatic stellate cells (HSC). Main methods: Immortalized mouse HSC lines JS1, JS2, and JS3 that were either TLR4 +/+, TLR4 -/-, or MyD88 -/- were transfected with NF-κB or AP-1 responsive luciferase reporter plasmids, followed by stimulation with 100 ng/ml lipopolysacchride (the exogenous TLR4 ligand) or 100 ng/ml HMGB1. The activation of NF-κB or AP-1 activities was determined by a dual-luciferase reporter assay system. The cells were also stimulated with LPS or HMGB1 and collected for the determination of chemotactic cytokine MCP-1 mRNA or proteins secretion. In a separate experiment, the cells were co-stimulated with 10 μg/ml TGF-β1 and LPS or HMGB1 and collected for assessment of fibrogenic mRNA and protein expression. Key findings: HMGB1 stimulation markedly up-regulated MCP-1 mRNA expression and protein secretion, and enhanced TGF-β1-stimulated collagen α2(I) and α-SMA expression in JS1 cells. This was associated with enhanced activation of NF-κB and AP-1 responsive luciferase reporters. On the contrary, JS2 and JS3 cells were hyporesponsive to both LPS and HGMB1 stimulation compared to JS1 cells. Significance: As an endogenous ligand of TLR4, HMGB1 activates TLR4 signaling in HSCs to enhance their inflammatory phenotype, indicating that TLR4 signaling need not rely solely on gut-derived LPS for activation during liver injury. HMGB1 also has a synergistic effect with TGF-β1 to stimulate fibrogenic protein expression, which is likely to be TLR4 dependent.

Original languageEnglish
Pages (from-to)207-212
Number of pages6
JournalLife Sciences
Volume91
Issue number5-6
DOIs
StatePublished - 4 Sep 2012

Keywords

  • Endogenous ligand
  • Hepatic stellate cells
  • High mobility group box-1
  • Toll like receptor 4

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