2015年1月16日訊 /生物谷BIOON/ --本文亮點：
M2型丙酮酸激酶四聚化能逆轉細菌內毒素LPS引起的Warburg效應
M2型丙酮酸激酶在穩定Hif-1α 和調節Hif-1α 下遊的靶基因表達過程中具有重要作用
M2型丙酮酸激酶四聚化能減弱細菌內毒素LPS引起的M1型巨噬細胞反應
M2型丙酮酸激酶是激活的巨噬細胞糖酵解代謝途徑轉變的重要決定因子
作為天然免疫系統中的一員，巨噬細胞主要負責清除感染病原體。但是其自身也分為兩類種群，即以分泌TNF-α，IL-1β等促炎性細胞因子為主的M1型巨噬細胞和以分泌IL-10等抗炎性細胞因子為主的M2型巨噬細胞。當巨噬細胞接收到細菌內毒素LPS信號後，其受體Toll樣受體4（TLR4，Toll-like receptor）啟動一系列細胞信號通路，並改變了巨噬細胞的代謝活力。
研究人員發現細菌內毒素LPS可以誘導巨噬細胞內大量表達M2型丙酮酸激酶（PKM2，Pyruvate Kinase M2），而丙酮酸激酶是葡萄糖酵解過程中重要的調控酶。通過DASA-58和TEPP-46兩種小分子激活劑將M2型丙酮酸激酶激活後，巨噬細胞中由內毒素LPS誘導產生的Hif-1α 和IL-1β 顯著減少，而且由Hif-1α 啟動的下遊靶基因的表達也同時減少。此外M2型丙酮酸激酶的激活也降低了由內毒素LPS引起的促炎性M1型巨噬細胞表型，相應的卻促進了抗炎性的M2型巨噬細胞表型。
研究人員深入研究之後發現當巨噬細胞被內毒素LPS處理後，胞內的M2型丙酮酸激酶會與Hif-1α形成複合體，並與IL-1β基因的促進子區域結合，但是當M2型丙酮酸激酶被激活後，這個現象就消失了。
細菌內毒素LPS還能引起細胞代謝向糖酵解方向轉變以及增加琥珀酸的積累。然而在體內實驗中通過TEPP-46激活M2型丙酮酸激酶能夠抑制由LPS和鼠傷寒沙門氏菌引起的IL-1β產生，卻增加IL-10的產生。綜上，M2型丙酮酸激酶在細菌內毒素LPS引起的炎症反應和巨噬細胞激活過程中扮演了至關重要的角色。（生物谷Bioon.com）
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生物谷推薦的英文摘要：
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.