Modulation of PKM activity affects the differentiation of TH17 cells
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). TH17 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 TH17 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 TH17 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.
Source: Signal Transduction Knowledge Environment - Category: Science Authors: Seki, S. M., Posyniak, K., McCloud, R., Rosen, D. A., Fernandez-Castaneda, A., Beiter, R. M., Serbulea, V., Nanziri, S. C., Hayes, N., Spivey, C., Gemta, L., Bullock, T. N. J., Hsu, K.-L., Gaultier, A. Tags: STKE Research Articles Source Type: news