2. Academic Validation
  3. Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages

Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages

  • Cell Metab. 2015 Jan 6;21(1):65-80. doi: 10.1016/j.cmet.2014.12.005.
Eva M Palsson-McDermott 1,  Anne M Curtis 1,  Gautam Goel 2,  Mario A R Lauterbach 1,  Frederick J Sheedy 3,  Laura E Gleeson 3,  Mirjam W M van den Bosch 1,  Susan R Quinn 1,  Raquel Domingo-Fernandez 1,  Daniel G W Johnston 1,  Jian-Kang Jiang,  William J Israelsen 4,  Joseph Keane 3,  Craig Thomas 5,  Clary Clish 6,  Matthew Vander Heiden,  Ramnik J Xavier 2,  Luke A J O'Neill 7
Affiliations

Affiliations

  • 1 School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin 2, Ireland.
  • 2 Centre for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Gastrointestinal Unit and Centre for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 3 Department of Clinical Medicine, School of Medicine, Trinity College, Dublin 2, Ireland.
  • 4 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 5 National Institutes of Health (NIH), Chemical Genomics Centre, National Centre for Advancing Translational Sciences, NIH, Bethesda, MD 20892, USA.
  • 6 Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 7 School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin 2, Ireland. Electronic address: [email protected].
PMID: 25565206 DOI: 10.1016/j.cmet.2014.12.005
Abstract

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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