title: Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages.
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.
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Palsson-McDermott
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Curtis
authors.affiliation: 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.
authors.forename: Gautam
authors.initials: G
authors.lastname: Goel
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Mario A R
authors.initials: MA
authors.lastname: Lauterbach
authors.affiliation: Department of Clinical Medicine, School of Medicine, Trinity College, Dublin 2, Ireland.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Sheedy
authors.affiliation: Department of Clinical Medicine, School of Medicine, Trinity College, Dublin 2, Ireland.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Gleeson
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Mirjam W M
authors.initials: MW
authors.lastname: van den Bosch
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Quinn
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Raquel
authors.initials: R
authors.lastname: Domingo-Fernandez
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Daniel G W
authors.initials: DG
authors.lastname: Johnston
authors.forename: Jian-Kang
authors.initials: JK
authors.lastname: Jiang
authors.affiliation: National Institutes of Health (NIH), Chemical Genomics Centre, National Centre for Advancing Translational Sciences, NIH, Bethesda, MD 20892, USA.
authors.forename: Jain-Kang
authors.initials: JK
authors.lastname: Jiang
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Israelsen
authors.affiliation: Department of Clinical Medicine, School of Medicine, Trinity College, Dublin 2, Ireland.
authors.forename: Joseph
authors.initials: J
authors.lastname: Keane
authors.affiliation: National Institutes of Health (NIH), Chemical Genomics Centre, National Centre for Advancing Translational Sciences, NIH, Bethesda, MD 20892, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Clary
authors.initials: C
authors.lastname: Clish
authors.forename: Matthew
authors.initials: M
authors.lastname: Vander Heiden
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Vanden Heiden
authors.affiliation: 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.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin 2, Ireland. Electronic address: laoneill@tcd.ie.
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002478:Cells, Cultured; D020536:Enzyme Activators / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006019:Glycolysis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011770:Pyruvate Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012486:Salmonella typhimurium / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism
chemical_list: D020536:Enzyme Activators; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D011770:Pyruvate Kinase