Functional Linkage of Cirrhosis-Predictive Single Nucleotide Polymorphisms of Toll-Like Receptor 4 to Hepatic Stellate Cell Responses
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UNLABELLED: In a recent study, a single nucleotide polymorphism (SNP) of the Toll-like receptor 4 (TLR4) gene (c.1196C>T [rs4986791, p.T399I]) emerged as conferring protection from fibrosis progression compared to a major, wild-type (WT) CC allele (p.T399). The present study examined the functional linkage of this SNP, along with another common, highly cosegregated TLR4 SNP (c.896A>G [rs4986790, p.D299G]), to hepatic stellate cell (HSC) responses. Both HSCs from TLR4(-/-) mice and a human HSC line (LX-2) reconstituted with either TLR4 D299G and/or T399I complementary DNAs were hyporesponsive to lipopolysaccharide (LPS) stimulation compared to those expressing WT TLR4, as assessed by the expression and secretion of LPS-induced inflammatory and chemotactic cytokines (i.e., monocyte chemoattractant protein-1, interleukin-6), down-regulation of bone morphogenic protein and the activin membrane-bound inhibitor expression (an inhibitory transforming growth factor beta pseudoreceptor), and activation of a nuclear factor kappaB (NF-kappaB)-responsive luciferase reporter. In addition, spontaneous apoptosis, as well as apoptosis induced by pathway inhibitors of NF-kappaB, extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase were greatly increased in HSCs from either TLR4(-/-) or myeloid differentiation factor 88(-/-) (a TLR adaptor protein) mice, as well as in murine HSCs expressing D299G and/or T399I SNPs; increased apoptosis in these lines was accompanied by decreased phospho-ERK and Bcl-2. CONCLUSION: TLR4 D299G and T399I SNPs that are associated with protection from hepatic fibrosis reduce TLR4-mediated inflammatory and fibrogenic signaling and lower the apoptotic threshold of activated HSCs. These findings provide a mechanistic link that explains how specific TLR4 SNPs may regulate the risk of fibrosis progression.
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Polymorphisms that attenuate HSC TLR4 activity reduce inflammatory signaling and are protective against fibrosis.
“Polymorphisms that attenuate HSC TLR4 activity reduce inflammatory signaling and are protective against fibrosis (32).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [32]
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- Authors
- Guo, J., Loke, J., Zheng, F., Hong, F., Yea, S., Fukata, M., Tarocchi, M., Abar, O. T., Huang, H., Sninsky, J. J., & Friedman, S. L.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Friedman, Scott L.
- Venue
- Hepatology
- Published
- 2009-03
- Volume
- 49
- Issue
- 3
- Pages
- 960-968
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC2891538
- OpenAlex
- W2076794498
- Semantic Scholar
- 2059afc5115efdff55a9c9be1562114523545359
- Cited by
- 217
- References
- 40
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 4 · 2023: 8 · 2022: 11 · 2021: 3 · 2020: 12 · 2019: 6 · 2018: 12 · 2017: 12 · 2016: 19 · 2015: 19 · 2014: 9 · 2013: 16 · 2012: 23
- FWCI
- 12.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Florence Research (University of Florence) (submittedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (P20AA017067)
- National Institute of General Medical Sciences (T32GM062754)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK056631, R01DK056621)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- TLR4, hepatic stellate cells, liver cirrhosis, liver fibrosis, lipopolysaccharide, NF-κB signaling, apoptosis, myeloid differentiation factor 88, interleukin-6, MCP-1, ERK, phosphatidylinositol 3-kinase, Bcl-2, TLR4 knockout mice
- MeSH terms
- Animals, Cell Line, Cells, Cultured, Disease Models, Animal, Humans, Lipopolysaccharides, Liver Cirrhosis, Membrane Proteins, Signal Transduction, Interleukin-6, NF-kappa B, Apoptosis, Mice, Knockout, Chemokine CCL2, Polymorphism, Single Nucleotide, Toll-Like Receptor 4, Mice, Myeloid Differentiation Factor 88, Hepatic Stellate Cells
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