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Functional Linkage of Cirrhosis-Predictive Single Nucleotide Polymorphisms of Toll-Like Receptor 4 to Hepatic Stellate Cell Responses
Open accessAbstract
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 (32).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [32]
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Metadata
- 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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