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Fibrogenesis & Tissue Repair
Published in: Fibrogenesis & Tissue Repair 1/2016

Open Access 01-12-2016 | Research

Transcriptomic analysis of the effects of Toll-like receptor 4 and its ligands on the gene expression network of hepatic stellate cells

Authors: Yangyang Ouyang, Jinsheng Guo, Chenzhao Lin, Jie Lin, Yirong Cao, Yuanqin Zhang, Yujin Wu, Shiyao Chen, Jiyao Wang, Luonan Chen, Scott L. Friedman

Published in: Fibrogenesis & Tissue Repair | Issue 1/2016

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Abstract

Background

Intact Toll-like receptor 4 (TLR4) has been identified in hepatic stellate cells (HSCs), the primary fibrogenic cell type in liver. Here, we investigated the impact of TLR4 signaling on the gene expression network of HSCs by comparing the transcriptomic changes between wild-type (JS1) and TLR4 knockout (JS2) murine HSCs in response to two TLR4 ligands, lipopolysacchride (LPS), or high-mobility group box 1 (HMGB1).

Results

Whole mouse genome microarray was performed for gene expression analysis. Gene interaction and co-expression networks were built on the basis of ontology and pathway analysis by Kyoto Encyclopedia of Genes and Genomes (KEGG). Gene expression profiles are markedly different between Wild type (JS1) and TLR4 knockout (JS2) HSCs under basal conditions or following stimulation with LPS or HMGB1. The differentially expressed genes between TLR4 intact and null HSCs were enriched in signaling pathways including p53, mTOR, NOD-like receptor, Jak-STAT, chemokine, focal adhesion with some shared downstream kinases, and transcriptional factors. Venn analysis revealed that TLR4-dependent, LPS-responsive genes were clustered into pathways including Toll-like receptor and PI3K-Akt, whereas TLR4-dependent, HMGB1-responsive genes were clustered into pathways including metabolism and phagosome signaling. Genes differentially expressed that were categorized to be TLR4-dependent and both LPS- and HMGB1-responsive were enriched in cell cycle, ubiquitin mediated proteolysis, and mitogen-activated protein kinase (MAPK) signaling pathways.

Conclusions

TLR4 mediates complex gene expression alterations in HSCs. The affected pathways regulate a wide spectrum of HSC functions, including inflammation, fibrogenesis, and chemotaxis, as well as cell growth and metabolism. There are common and divergent regulatory signaling downstream of LPS and HMGB1 stimulation via TLR4 on HSCs. These findings emphasize the complex cascades downstream of TLR4 in HSCs that could influence their cellular biology and function.
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Metadata
Title
Transcriptomic analysis of the effects of Toll-like receptor 4 and its ligands on the gene expression network of hepatic stellate cells
Authors
Yangyang Ouyang
Jinsheng Guo
Chenzhao Lin
Jie Lin
Yirong Cao
Yuanqin Zhang
Yujin Wu
Shiyao Chen
Jiyao Wang
Luonan Chen
Scott L. Friedman
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Fibrogenesis & Tissue Repair / Issue 1/2016
Electronic ISSN: 1755-1536
DOI
https://doi.org/10.1186/s13069-016-0039-z

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