Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of Toll-like receptor 4 to hepatic stellate cell responses.
Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of Toll-like receptor 4 to hepatic stellate cell responses.
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Toll样受体4的肝硬化预测单核苷酸多态性与肝星状细胞反应的功能联系。
DOI：
10.1002/hep.22697
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发表时间：
2009-03
期刊：
影响因子：
13.5
通讯作者：
Friedman, Scott L.
中科院分区：
文献类型：
--
作者：
Guo, Jinsheng;Loke, Johnny;Zheng, Feng;Hong, Feng;Yea, Steven;Fukata, Masayuki;Tarocchi, Mirko;Abar, Olivia T.;Huang, Hongjin;Sninsky, John J.;Friedman, Scott L.
在最近的一项研究中，与主要的野生型（WT）CC等位基因（p.T399）相比，Toll样受体4（TLR4）基因的一个单核苷酸多态性（SNP）（c.1196C>T [rs4986791，p.T399I]）显示出对纤维化进展具有保护作用。本研究检测了该SNP以及另一个常见的、高度共分离的TLR4 SNP（c.896A>G [rs4986790，p.D299G]）与肝星状细胞（HSC）反应的功能联系。与表达野生型TLR4的细胞相比，来自TLR4 - / - 小鼠的HSCs以及用人TLR4 D299G和/或T399I互补DNA重组的人HSC系（LX - 2）对脂多糖（LPS）刺激反应低下，这通过LPS诱导的炎症和趋化细胞因子（即单核细胞趋化蛋白 - 1、白细胞介素 - 6）的表达和分泌、骨形态发生蛋白的下调以及激活素膜结合抑制剂表达（一种抑制性转化生长因子β假受体）以及核因子κB（NF - κB）响应的荧光素酶报告基因的激活来评估。此外，来自TLR4 - / - 或髓样分化因子88 - / - （一种TLR衔接蛋白）小鼠的HSCs以及表达D299G和/或T399I SNPs的小鼠HSCs中，自发凋亡以及由NF - κB、细胞外信号调节激酶（ERK）和磷脂酰肌醇3 - 激酶途径抑制剂诱导的凋亡大大增加；这些细胞系中凋亡增加的同时伴有磷酸化ERK和Bcl - 2的减少。
与防止肝纤维化相关的TLR4 D299G和T399I SNPs可减少TLR4介导的炎症和纤维化信号传导，并降低活化的HSCs的凋亡阈值。这些发现提供了一种机制上的联系，解释了特定的TLR4 SNPs如何调节纤维化进展的风险。
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-κ)–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. 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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