Modulation of PKM activity affects the differentiation of T H 17 cells.

Autor: Seki SM; Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.; Graduate Program in Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.; Medical Scientist Training Program, University of Virginia, Charlottesville, VA 22908, USA., Posyniak K; Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA., McCloud R; Department of Chemistry, University of Virginia, Charlottesville, VA 22908, USA., Rosen DA; Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.; Graduate Program in Pharmacological Sciences, University of Virginia, Charlottesville, VA 22908, USA., Fernández-Castañeda A; Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.; Graduate Program in Neuroscience, University of Virginia, Charlottesville, VA 22908, USA., Beiter RM; Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.; Graduate Program in Neuroscience, University of Virginia, Charlottesville, VA 22908, USA., Serbulea V; Graduate Program in Pharmacological Sciences, University of Virginia, Charlottesville, VA 22908, USA., Nanziri SC; Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA., Hayes N; Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA., Spivey C; Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA., Gemta L; Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.; Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Bullock TNJ; Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.; Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Hsu KL; Department of Chemistry, University of Virginia, Charlottesville, VA 22908, USA., Gaultier A; Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA. ag7h@virginia.edu.
Jazyk: angličtina
Zdroj: Science signaling [Sci Signal] 2020 Oct 27; Vol. 13 (655). Date of Electronic Publication: 2020 Oct 27.
DOI: 10.1126/scisignal.aay9217
Abstrakt: Small molecules that promote the metabolic activity of the pyruvate kinase isoform PKM2, such as TEPP-46 and DASA-58, limit tumorigenesis and inflammation. To understand how these compounds alter T cell function, we assessed their therapeutic activity in a mouse model of T cell-mediated autoimmunity that mimics multiple sclerosis (MS). T H 17 cells are believed to orchestrate MS pathology, in part, through the production of two proinflammatory cytokines: interleukin-17 (IL-17) and GM-CSF. We found that both TEPP-46 and DASA-58 suppressed the development of IL-17-producing T H 17 cells but increased the generation of those producing GM-CSF. This switch redirected disease pathology from the spinal cord to the brain. In addition, we found that activation of PKM2 interfered with TGF-β1 signaling, which is necessary for the development of T H 17 and regulatory T cells. Collectively, our data clarify the therapeutic potential of PKM2 activators in MS-like disease and how these agents alter T cell function.
(Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze: MEDLINE
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