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首页 » 炎症与疾病 » Cell Metabolism:Warburg效应新视角:M2型丙酮酸激酶如何调控细菌内毒素LPS引起的炎症

Cell Metabolism:Warburg效应新视角:M2型丙酮酸激酶如何调控细菌内毒素LPS引起的炎症

来源:生物谷 2015-01-16 17:00

2015年1月16日讯 /生物谷BIOON/ --本文亮点:

M2型丙酮酸激酶四聚化能逆转细菌内毒素LPS引起的Warburg效应

M2型丙酮酸激酶在稳定Hif-1α 和调节Hif-1α 下游的靶基因表达过程中具有重要作用

M2型丙酮酸激酶四聚化能减弱细菌内毒素LPS引起的M1型巨噬细胞反应

M2型丙酮酸激酶是激活的巨噬细胞糖酵解代谢途径转变的重要决定因子

 

作为天然免疫系统中的一员,巨噬细胞主要负责清除感染病原体。但是其自身也分为两类种群,即以分泌TNF-α,IL-1β等促炎性细胞因子为主的M1型巨噬细胞和以分泌IL-10等抗炎性细胞因子为主的M2型巨噬细胞。当巨噬细胞接收到细菌内毒素LPS信号后,其受体Toll样受体4(TLR4,Toll-like receptor)启动一系列细胞信号通路,并改变了巨噬细胞的代谢活力。

研究人员发现细菌内毒素LPS可以诱导巨噬细胞内大量表达M2型丙酮酸激酶(PKM2,Pyruvate Kinase M2),而丙酮酸激酶是葡萄糖酵解过程中重要的调控酶。通过DASA-58和TEPP-46两种小分子激活剂将M2型丙酮酸激酶激活后,巨噬细胞中由内毒素LPS诱导产生的Hif-1α 和IL-1β 显着减少,而且由Hif-1α 启动的下游靶基因的表达也同时减少。此外M2型丙酮酸激酶的激活也降低了由内毒素LPS引起的促炎性M1型巨噬细胞表型,相应的却促进了抗炎性的M2型巨噬细胞表型。

研究人员深入研究之后发现当巨噬细胞被内毒素LPS处理后,胞内的M2型丙酮酸激酶会与Hif-1α形成复合体,并与IL-1β基因的促进子区域结合,但是当M2型丙酮酸激酶被激活后,这个现象就消失了。

细菌内毒素LPS还能引起细胞代谢向糖酵解方向转变以及增加琥珀酸的积累。然而在体内实验中通过TEPP-46激活M2型丙酮酸激酶能够抑制由LPS和鼠伤寒沙门氏菌引起的IL-1β产生,却增加IL-10的产生。综上,M2型丙酮酸激酶在细菌内毒素LPS引起的炎症反应和巨噬细胞激活过程中扮演了至关重要的角色。(生物谷Bioon.com)

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生物谷推荐的英文摘要:

 

Cell Metabolism DOI: http://dx.doi.org/10.1016/j.cmet.2014.12.005

Pyruvate Kinase M2 Regulates Hif-1α Activity and IL-1β Induction and Is a Critical Determinant of the Warburg Effect in LPS-Activated Macrophages

Eva M. Palsson-McDermott, Anne M. Curtis, Gautam Goel, Mario A.R. Lauterbach, Frederick J. Sheedy, Laura E. Gleeson, Mirjam W.M. van den Bosch, Susan R. Quinn, Raquel Domingo-Fernandez, Daniel G.W. Johnston, Jain-kang Jiang, William J. Israelsen, Joseph Keane, Craig Thomas, Clary Clish, Matthew Vander Heiden, Ramnik J. Xavier, Luke A.J. O'Neill

Highlights

" oTetramerization of PKM2 reverses the LPS-induced Warburg effect

" oPKM2 plays a key role in stabilizing Hif-1α and regulates Hif-1α-dependent genes

" oTetramerization of PKM2 attenuates LPS-induced M1 macrophage traits

" oPKM2 is a critical determinant of glycolytic reprogramming in macrophages

Summary

Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. We show that LPS-induced PKM2 enters into a complex with Hif-1α, which can directly bind to the IL-1β promoter, an event that is inhibited by activation of PKM2. Both compounds inhibited LPS-induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1β production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.

 

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