脂多糖通过Toll样受体-4和NF-κB信号途径损害分离胰岛中朗格汉斯细胞的胰岛素基因表达
发布时间：2012-10-08 14:31:12浏览次数：3720次来源：吉林大学白求恩第二医院 上海市第六人民医院 摘自:2012;7(4):e36200. Epub 2012 Apr 27.
背景：2型糖尿病是以胰岛β细胞功能障碍为特征，并且与低度炎症反应有关。最近的观察表明，脂多糖（LPS）结合Toll样受体4（TLR4）激活的信号级联反应可以对胰岛β细胞产生毒性作用；然而，这些作用的分子机制尚不完全清楚。这项研究的目的是为了验证以下假设，即LPS可通过胰岛中活化的B细胞中的TLR4和核因子κ-轻链增强子（NF-κB）来改变胰岛素的基因表达。
方法/主要结果：将从人，大鼠和小鼠的胰岛中分离的朗格汉斯细胞暴露于LPS 24小时后呈现LPS剂量依赖性地胰岛素基因表达减少。这与小鼠和大鼠胰岛中胰十二指肠同型-1（PDX-1）mRNA表达及与禽类同源的哺乳动物MAFA/ L-MAF（MAFA）的下降有关。因此，LPS的暴露也可以减少葡萄糖诱导的胰岛素分泌。在TLR4缺陷的小鼠胰岛中并没有观察到LPS抑制胰岛素，PDX-1和MafA的表达，以及其对胰岛素分泌的抑制。在大鼠的胰岛中LPS可以通过抑制NF-κB途径，而不是p38丝裂原活化蛋白激酶（p38 MAPK）途径最终抑制β细胞基因表达。
结论/意义：我们的研究结果表明，在胰岛中LPS通过TLR4依赖性的方式，经过NF-κB的信号途径抑制了胰岛β细胞的基因表达，提出了肠道菌群可能影响胰岛β细胞功能的又一新机制。
Lipopolysaccharides impair insulin gene expression in isolated islets of Langerhans via Toll-Like Receptor-4 and NF-κB signalling.
BACKGROUND:Type 2 diabetes is characterized by pancreatic β-cell dysfunction and is associated with low-grade inflammation. Recent observations suggest that the signalling cascade activated by lipopolysaccharides (LPS) binding to Toll-Like Receptor 4 (TLR4) exerts deleterious effects on pancreatic β-cell function; however, the molecular mechanisms of these effects are incompletely understood. In this study, we tested the hypothesis that LPS alters insulin gene expression via TLR4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in islets.
METHODOLOGY/PRINCIPAL FINDINGS:A 24-h exposure of isolated human, rat and mouse islets of Langerhans to LPS dose-dependently reduced insulin gene expression. This was associated in mouse and rat islets with decreased mRNA expression of pancreas-duodenum homebox-1 (PDX-1) and mammalian homologue of avian MafA/l-Maf (MafA). Accordingly, LPS exposure also decreased glucose-induced insulin secretion. LPS repression of insulin, PDX-1 and MafA expression, as well as its inhibition of insulin secretion, were not observed in islets from TLR4-deficient mice. LPS inhibition of β-cell gene expression in rat islets was prevented by inhibition of the NF-κB pathway, but not the p38 mitogen-activated protein kinase (p38 MAPK) pathway.
CONCLUSIONS/SIGNIFICANCE:Our findings demonstrate that LPS inhibit β-cell gene expression in a TLR4-dependent manner and via NF-κB signaling in pancreatic islets, suggesting a novel mechanism by which the gut microbiota might affect pancreatic β-cell function.
链接: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0036200
