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【Hepatology】Hepatology：TLR4基因SNP与肝脏纤维化研
简介：
在最近的研究中，复旦大学中山医院消化科等发现纤维化的肝细胞to11样受体4基因（toll-like receptor 4 gene,TLR4)的单核苷酸多态性发生变化，主要的CC等位基因发生变异。研究者对这一单核苷酸多态性进行功能性的研究，并用肝脏stellate细胞作为研究模型。选取两种肝脏stellate细胞（ hepatic ste11ate ce11，HSC），一种是小鼠的TLR4-/-的HSC，一种是人类的HSC细胞系（LX-2），LX-2的特点是与野生型的HSC细胞相比该细胞系的TLR4D299G或T3991互补DNAs与脂多糖具有低反应性。与脂多糖的反应直接关系着肝细胞的炎症反应性。
结论：TLR4D299G和T399I的SNP与抵抗肝细胞纤维化的有关，并且与诱导TLR4介导的炎症反应与纤维生成信号，降低干细胞凋亡的信号阙值都有相当大的关联。这些研究结果为TLR4 SNP可能是调节肝脏纤维化的理论提供了实质性的分子证据。
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
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--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.)
Predictive SNP of TLR4 to HSC Responses.part1.rar (292.97k) 背景知识：
TLRs主要分布于骨髓细胞、淋巴组织，上皮细胞和树突状细胞等细胞表面，TLR2和TLR4是天然免疫受体家族中最早发现的成员。
TLR2识别多种病原体的成分，并将信号通过My88和TIRAP (TIR adaptor protein)传递到细胞内发挥作用；最近在TLR2缺陷小鼠的研究提示，TLR2拮抗物可能具有抵抗白色念珠菌感染的能力。
TLR3能够识别病毒双链RNA及Poly I:C，可通过产生I类干扰素发挥抗病毒作用；此外，TLR3和TLR4有共同的细胞内信号传导途径，可以解释在严重病毒感染时常常有针对细菌LPS的炎症反应。
TLR4可识别细茵的脂多糖（LPS），导致针对含有细菌LPS的免疫应答，同时介导炎症反应；TLR4信号传递方式分别为依赖My88和不依赖My88两种，抑制TLR4表达或应用其抑制剂可以减轻由细菌感染所致的系统炎症反应，目前有研究进行治疗探索。
TLR5 识别细菌鞭毛蛋白；
TLR9识别细菌CpG DNA。
TLR7 和 TLR8 能识别一些人工合成的抗病毒小分子。
Predictive SNP of TLR4 to HSC Responses.part2.rar (81.97k) [标签:content1][标签:content2]
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作者:admin@医学,生命科学 2011-08-29 17:11
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