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生物通报道，复旦大学上海医学院附属中山医院内科肝病科，消化科，美国西奈山医学院老年病研究部的科学家联手在顶级的肝病论文期刊Hepatology（11月13日刊）（影响因子10.734）发表文章，解析肝细胞toll样受体4单核甘酸多态性与肝硬化间的功能关系。
原文摘要：Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of toll-like receptor 4 to hepatic stellate cell responses
Jinsheng Guo 1 2, Johnny Loke 1, Feng Zheng 3, Feng Hong 1, Steven Yea 1, Massayuki Fugita 1, Mirko Tarocchi 1, Olivia T. Abar 4, Hongjin Huang 4, John J. Sninsky 4, Scott L. Friedman 1 *§
1Division of Liver Diseases, Zhongshan Hospital, Department of Internal Medicine, Shanghai Medical College, Fudan University, Shanghai, China
2Division of Digestive Diseases, Zhongshan Hospital, Department of Internal Medicine, Shanghai Medical College, Fudan University, Shanghai, China
3Department of Geriatrics, Mount Sinai School of Medicine, New York, NY
4Celera, Alameda, CA
【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 pseudoreceptor), and activation of a nuclear factor B (NF-B)-responsive luciferase reporter. In addition, spontaneous apoptosis, as well as apoptosis induced by pathway inhibitors of NF-B, 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. (HEPATOLOGY 2009.)
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Received: 6 July 2008; Accepted: 10 October 2008
Digital Object Identifier (DOI)
10.1002/hep.22697
