Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of toll-like receptor 4 to hepatic stellate cell responses

Jinsheng Guo, Johnny C. Loke, Feng Zheng, Feng Hong, Steven Yea, Masayuki Fukata, Mirko Tarocchi, Olivia T. Abar, Hongjin Huang, John J. Sninsky, Scott I. Friedman

Research output: Contribution to journalArticle

155 Citations (Scopus)

Abstract

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 β pseudoreceptor), and activation of a nuclear factor κB (NF-κB)-responsive luciferase reporter. In addition, spontaneous apoptosis, as well as apoptosis induced by pathway inhibitors of NF-κB, 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.

Original languageEnglish (US)
Pages (from-to)960-968
Number of pages9
JournalHepatology
Volume49
Issue number3
DOIs
StatePublished - 2009
Externally publishedYes

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Hepatic Stellate Cells
Toll-Like Receptor 4
Single Nucleotide Polymorphism
Fibrosis
Apoptosis
Lipopolysaccharides
Myeloid Differentiation Factor 88
Phosphatidylinositol 3-Kinase
Activins
Chemokine CCL2
Mitogen-Activated Protein Kinase 1
Extracellular Signal-Regulated MAP Kinases
Transforming Growth Factors
Luciferases
Chemokines
Interleukin-6
Membrane Proteins
Down-Regulation
Complementary DNA
Alleles

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of toll-like receptor 4 to hepatic stellate cell responses. / Guo, Jinsheng; Loke, Johnny C.; Zheng, Feng; Hong, Feng; Yea, Steven; Fukata, Masayuki; Tarocchi, Mirko; Abar, Olivia T.; Huang, Hongjin; Sninsky, John J.; Friedman, Scott I.

In: Hepatology, Vol. 49, No. 3, 2009, p. 960-968.

Research output: Contribution to journalArticle

Guo, J, Loke, JC, Zheng, F, Hong, F, Yea, S, Fukata, M, Tarocchi, M, Abar, OT, Huang, H, Sninsky, JJ & Friedman, SI 2009, 'Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of toll-like receptor 4 to hepatic stellate cell responses', Hepatology, vol. 49, no. 3, pp. 960-968. https://doi.org/10.1002/hep.22697
Guo, Jinsheng ; Loke, Johnny C. ; Zheng, Feng ; Hong, Feng ; Yea, Steven ; Fukata, Masayuki ; Tarocchi, Mirko ; Abar, Olivia T. ; Huang, Hongjin ; Sninsky, John J. ; Friedman, Scott I. / Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of toll-like receptor 4 to hepatic stellate cell responses. In: Hepatology. 2009 ; Vol. 49, No. 3. pp. 960-968.
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abstract = "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 β pseudoreceptor), and activation of a nuclear factor κB (NF-κB)-responsive luciferase reporter. In addition, spontaneous apoptosis, as well as apoptosis induced by pathway inhibitors of NF-κB, 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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AU - Guo, Jinsheng

AU - Loke, Johnny C.

AU - Zheng, Feng

AU - Hong, Feng

AU - Yea, Steven

AU - Fukata, Masayuki

AU - Tarocchi, Mirko

AU - Abar, Olivia T.

AU - Huang, Hongjin

AU - Sninsky, John J.

AU - Friedman, Scott I.

PY - 2009

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AB - 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 β pseudoreceptor), and activation of a nuclear factor κB (NF-κB)-responsive luciferase reporter. In addition, spontaneous apoptosis, as well as apoptosis induced by pathway inhibitors of NF-κB, 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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