权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of IL-4-induced human macrophage polarization by acetyl-CoA and AMP-activated protein kinase

乙酰辅酶 A 和 AMP 激活蛋白激酶对 IL-4 诱导的人巨噬细胞极化的调节

基本信息

批准号：
260847914
负责人：
Privatdozent Dr. Dmitry Namgaladze
金额：
--
依托单位：
Institut für Biochemie I: Pathobiochemie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/260847914?language=en
关键词：
Regulation IL induced human macrophage

项目摘要

Macrophages respond to pro- versus anti-inflammatory stimuli (macrophage polarization) by altering their metabolism. In turn, intermediate metabolites regulate intracellular signaling and gene expression. Thus, acetyl-CoA, besides its role in energy generation by driving the citrate cycle, is a substrate for protein and histone acetylation. ATP citrate lyase (ACLY), an enzyme responsible for cytosolic acetyl-CoA generation, support gene expression through histone acetylation in responses to altered nutrient levels in cancer cells and adipocytes, but also to the cytokine IL-4 in murine macrophages. Our preliminary data show an IL-4-stimulated expression of arachidonate 15-lipoxygenase (ALOX15) to be sensitive to ACLY inhibition. However, the impact of ACLY and acetyl-CoA on IL-4-induced human macrophage polarization remains unclear. Furthermore, we have previously shown that AMP-dependent protein kinase (AMPK) - mediated inhibition of ALOX15 expression in IL-4-stimulated macrophages may partly occur through altered histone acetylation. In this proposal we aim to elucidate the influence of ACLY-driven acetyl-CoA generation on human macrophage polarization in response to IL-4. We postulate that ACLY, by physically associating with gene regulatory elements on chromatin, may locally regulate histone acetylation on a subset of IL-4-responsive genes. Second we reveal an altered pattern of protein acetylation, dependent on ACLY-driven acetyl-CoA. This will be address in a proteomic screen. Third, we investigate the influence of AMPK on protein acetylation. We suggest that AMPK inhibits the activity of ACLY, thereby eliciting changes of histone acetylation and thus, gene expression. Our study adds to understand how metabolism and, in particular, acetyl-CoA generation, connects to macrophage polarization.

巨噬细胞通过改变它们的代谢来响应促炎刺激与抗炎刺激（巨噬细胞极化）。反过来，中间代谢物调节细胞内信号传导和基因表达。因此，乙酰辅酶A，除了其在通过驱动柠檬酸循环产生能量中的作用之外，还是蛋白质和组蛋白乙酰化的底物。ATP柠檬酸裂解酶（ACLY）是一种负责细胞溶质乙酰辅酶A生成的酶，通过组蛋白乙酰化支持基因表达，以响应癌细胞和脂肪细胞中改变的营养水平，以及鼠巨噬细胞中的细胞因子IL-4。我们的初步数据显示，IL-4刺激的花生四烯酸15-脂氧合酶（ALOX 15）的表达对ACLY抑制敏感。然而，ACLY和乙酰辅酶A对IL-4诱导的人巨噬细胞极化的影响仍不清楚。此外，我们以前已经表明，AMP依赖性蛋白激酶（AMPK）介导的抑制ALOX 15表达在IL-4刺激的巨噬细胞可能部分发生通过改变组蛋白乙酰化。在这个提议中，我们的目的是阐明ACLY驱动的乙酰辅酶A的产生对人巨噬细胞极化响应IL-4的影响。我们假设，ACLY，通过物理关联与染色质上的基因调控元件，可以局部调节组蛋白乙酰化的一个子集的IL-4反应基因。第二，我们揭示了一种改变的蛋白质乙酰化模式，依赖于ACLY驱动的乙酰辅酶A。这将在蛋白质组学筛选中得到解决。第三，我们研究了AMPK对蛋白质乙酰化的影响。我们认为AMPK抑制ACLY的活性，从而引起组蛋白乙酰化的变化，从而引起基因表达的变化。我们的研究增加了对代谢，特别是乙酰辅酶A生成如何与巨噬细胞极化联系的理解。