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Sci Signal ; 13(655)2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33109748

RESUMO

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-ß1 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.


Assuntos
Diferenciação Celular/imunologia , Esclerose Múltipla/imunologia , Piruvato Quinase/imunologia , Transdução de Sinais/imunologia , Células Th17/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Feminino , Masculino , Camundongos , Camundongos Knockout , Esclerose Múltipla/genética , Piridazinas/farmacologia , Pirróis/farmacologia , Piruvato Quinase/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/imunologia
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