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

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

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157 Scopus citations

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 - Jun 24 2009

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ASJC Scopus subject areas

  • Hepatology

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Guo, J., Loke, J., Zheng, F., Hong, F., Yea, S., Fukata, M., Tarocchi, M., Abar, O. T., Huang, H., Sninsky, J. J., & Friedman, S. I. (2009). Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of toll-like receptor 4 to hepatic stellate cell responses. Hepatology, 49(3), 960-968. https://doi.org/10.1002/hep.22697