Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages
By E. Palsson-McDermott, A. Curtis, G. Goel, M. Lauterbach, Frederick J. Sheedy, Laura E. Gleeson, Mirjam W. M. van den Bosch, Susan R. Quinn, R. Domingo-Fernández, Daniel GW Johnson and 8 more. Cell Metabolism, 2015
953 citations recorded by the source corpus.
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 pro-inflammatory 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, whilst boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.
Subfields: Cancer Research, Immunology, Physiology
View Paper: https://www.semanticscholar.org/paper/98a962d04f4ebd1c2d2ca06588ca162d59e6c02e
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In Immunology
- P. Vieira
- M. Saraiva
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- R. Sánchez-Rodríguez
- Tommaso Scolaro
- A. Viola
- Alessandra Castegna
In Physiology
Citations in the corpus
- Biology and therapeutic potential of interleukin-10 (2019, background): “The LPS-induced metabolic regulator pyruvate kinase isozyme M2 (PKM2) was shown to inhibit the cellular glycolytic reprogramming, succinate accumulation, and IL-1β production, while favoring IL-10 production by macrophages (Palsson-McDermott et al., 2015).”
- The Metabolic Signature of Macrophage Responses (2019, background): “M1 macrophages express predominantly the PFKFB3 isoform (53) which, if compared to the other isoforms, less efficiently catalyzes the conversion of fructose-2,6-bisphosphate in fructose 6phosphate, enhancing the glycolytic flux.”