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Cited by 651Immune Response and InflammationLiver physiology and pathologyAlcohol Consumption and Health Effects

Toll-Like Receptor 4 Mediates Inflammatory Signaling by Bacterial Lipopolysaccharide in Human Hepatic Stellate Cells

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Paik, Yong-Han, Schwabe, Robert F., Bataller, Ramón, Russo, Maria P., Jobin, Christian, Brenner, David A.·2003·Hepatology
DOI 10.1053/jhep.2003.50182
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Abstract

Bacterial lipopolysaccharide (LPS) stimulates Kupffer cells and participates in the pathogenesis of alcohol–induced liver injury. However, it is unknown whether LPS directly affects hepatic stellate cells (HSCs), the main fibrogenic cell type in the injured liver. This study characterizes LPS–induced signal transduction and proinflammatory gene expression in activated human HSCs. Culture–activated HSCs and HSCs isolated from patients with hepatitis C virus–induced cirrhosis express LPS–associated signaling molecules, including CD14, toll–like receptor (TLR) 4, and MD2. Stimulation of culture–activated HSCs with LPS results in a rapid and marked activation of NF–κB, as assessed by in vitro kinase assays for IκB kinase (IKK), IκBα steady–state levels, p65 nuclear translocation, NF–κB–dependent luciferase reporter gene assays, and electrophoretic mobility shift assays. Lipid A induces NF–κB activation in a similar manner. Both LPS– and lipid A–induced NF–κB activation is blocked by preincubation with either anti–TLR4 blocking antibody (HTA125) or Polymyxin B. Lipid A induces NF–κB activation in HSCs from TLR4–sufficient (C3H/OuJ) mice but not from TLR4–deficient (C3H/HeJ) mice. LPS also activates c–Jun N–terminal kinase (JNK), as assessed by in vitro kinase assays. LPS up–regulates IL–8 and MCP–1 gene expression and secretion. LPS–induced IL–8 secretion is completely inhibited by the IκB super repressor (Ad5IκB) and partially inhibited by a specific JNK inhibitor, SP600125. LPS also up–regulates cell surface expression of ICAM–1 and VCAM–1. In conclusion, human activated HSCs utilize components of TLR4 signal transduction cascade to stimulate NF–κB and JNK and up–regulate chemokines and adhesion molecules. Thus, HSCs are a potential mediator of LPS–induced liver injury.

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Crossref · 10.1053/jhep.2003.50182

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  • CCL2 expression is increased in activated HSCs.

    “and the expression of CCL2 is increased in activated HSCs,37”

    From Sphingosine Kinase 1 Aggravates Liver Fibrosis by Mediating Macrophage Recruitment and Polarization (2024) · cites this paper as [37]

    The Discussion reports that LPS induced MCP-1 (CCL2) mRNA and protein expression in activated human HSCs. It does not show that CCL2 expression increases as HSCs become activated, or that activated HSCs express more CCL2 than quiescent HSCs. (LLM, conf=0.84)

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  • When exposed to low levels of LPS, activated HSCs activate NF-κB, secrete pro-inflammatory cytokines including IL-8, upregulate ICAM-1 and VCAM-1, and suppress the TGFβ pseudoreceptor Bambi.

    “When exposed to low levels of LPS, aHSCs activate the NF-κB pathway, secrete pro-inflammatory cytokines including IL-8, upregulate leukocyte adhesion molecules ICAM-1 and VCAM-1 and suppress the TGFβ pseudoreceptor Bambi (30, 31).”

    From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [30]

  • Elevated LPS activated NF-κB in hepatic stellate cells (HSC) via TLR-4 signaling, followed by production of inflammatory chemokines and expression of cell surface adhesion molecules.

    “Elevated LPS activated NF-κB in HSC via TLR-4 signaling, followed by production of inflammatory chemokines and expression of cell surface adhesion molecules [63, 64] (Fig. 2).”

    From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [63]

  • Stimulation of hepatic stellate cells by LPS results in upregulation of multiple chemokines and adhesion molecules.

    “This results in an upregulation of multiple chemokines and adhesion molecules.232”

    From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [232]

  • Hepatic stellate cells can be directly stimulated by bacterial LPS, mainly through induction of TLR4 signaling.

    “Hepatic stellate cells, the main fibrosis-inducing cell line in the liver, can also be directly stimulated by bacterial lipopolysaccharide (LPS), mainly through induction of TLR4 signaling.”

    From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [232]

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Research works printed but not linked: 1

  1. Hellerbrand C, Jobin C, Licato LL, Sartor RB, Brenner DA. Cytokines induce NF-B in activated but not in quiescent rat hepatic stellate cells. Am J Physiol 1998;275:G269-G278.

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Authors
Paik, Y.-H., Schwabe, R. F., Bataller, R., Russo, M. P., Jobin, C., & Brenner, D. A.
Affiliations
University of North Carolina at Chapel Hill (US)
Corresponding author
Brenner, David A.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2003-05
Volume
37
Issue
5
Pages
1043-1055
ISSN
0270-9139 (ISSN-L)
DOI
10.1053/jhep.2003.50182
OpenAlex
W2094133741
Cited by
651
References
51
Citations by year
2026: 11 · 2025: 17 · 2024: 20 · 2023: 20 · 2022: 18 · 2021: 27 · 2020: 34 · 2019: 25 · 2018: 26 · 2017: 36 · 2016: 33 · 2015: 55 · 2014: 25 · 2013: 39 · 2012: 26
FWCI
8.33
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 4506 d)
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
Funders
  • American Liver Foundation
  • Yonsei University
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
Keywords
TLR4, lipopolysaccharide, hepatic stellate cells, NF-κB activation, c-Jun N-terminal kinase, lipid A, CD14, MD-2, liver fibrosis, hepatitis C cirrhosis, interleukin-8, MCP-1, ICAM-1, VCAM-1, chemokine expression, adhesion molecules, alcohol-induced liver injury, TLR4-deficient mice
MeSH terms
Animals, Blood Proteins, Cells, Cultured, Humans, Lipopolysaccharides, Liver Cirrhosis, Membrane Glycoproteins, Mice, Inbred C3H, Receptors, Cell Surface, Signal Transduction, Up-Regulation, Interleukin-8, NF-kappa B, Intercellular Adhesion Molecule-1, Transcription Factor AP-1, Chemokine CCL2, Lipopolysaccharide Receptors, Vascular Cell Adhesion Molecule-1, Mitogen-Activated Protein Kinases, Hepatocytes, Drosophila Proteins, JNK Mitogen-Activated Protein Kinases, Toll-Like Receptors, Toll-Like Receptor 4, Mice

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