Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages
| Autor: | Luke A. J. O'Neill, Clary B. Clish, Mario A.R. Lauterbach, Susan R. Quinn, Frederick J. Sheedy, Anne M. Curtis, Daniel G.W. Johnston, Joseph Keane, Gautam Goel, Craig J. Thomas, Raquel Domingo-Fernandez, William J. Israelsen, Matthew G. Vander Heiden, Eva M. Palsson-McDermott, Mirjam W.M. van den Bosch, Laura E. Gleeson, Ramnik J. Xavier, Jian-kang Jiang |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Lipopolysaccharides
Salmonella typhimurium Physiology Interleukin-1beta Pyruvate Kinase Enzyme Activators Gene Expression Bone Marrow Cells Biology PKM2 Article Proinflammatory cytokine Enzyme activator 03 medical and health sciences Mice 0302 clinical medicine Animals Glycolysis RNA Messenger Promoter Regions Genetic Molecular Biology Cells Cultured 030304 developmental biology 0303 health sciences Macrophages Cell Biology Macrophage Activation M2 Macrophage Hypoxia-Inducible Factor 1 alpha Subunit Warburg effect Cell biology Mice Inbred C57BL Toll-Like Receptor 4 030220 oncology & carcinogenesis TLR4 lipids (amino acids peptides and proteins) Pyruvate kinase Protein Binding |
| Popis: | SummaryMacrophages 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. |
| Databáze: | OpenAIRE |
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