Interleukin-10(IL-10)is the most potent anti-inflammatory cytokine in the body and plays an essential role in determining outcomes of many inflammatory diseases.Cellular metabolism is a critical determinant of immune ...Interleukin-10(IL-10)is the most potent anti-inflammatory cytokine in the body and plays an essential role in determining outcomes of many inflammatory diseases.Cellular metabolism is a critical determinant of immune cell function;however,it is currently unclear whether metabolic processes are specifically involved in IL-10 production.In this study,we aimed to find the central metabolic molecule regulating IL-10 production of macrophages,which are the main producers of IL-10.Transcriptomic analysis identified that metabolic changes were predominantly enriched in Kupffer cells at the early inflammatory phase of a mouse endotoxemia model.Among them,pyruvate dehydrogenase kinase(PDK)-dependent acute glycolysis was negatively involved in IL-10 production.Inhibition or knockdown of PDK selectively increased macrophage IL-10 expression.Mechanistically,PDK inhibition increased IL-10 production via profound phosphorylation of adenosine monophosphate(AMP)-activated protein kinase alpha 1(AMPKα1)by restricting glucose uptake in lipopolysaccharide-stimulated macrophages.AMPKα1 consequently activated p38 mitogen-activated protein kinase,c-Jun N-terminal kinase,and cyclic AMP-responsive element-binding protein to regulate IL-10 production.Our study uncovers a previously unknown regulatory mechanism of IL-10 in activated macrophages involving an immunometabolic function of PDK.展开更多
基金supported by Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science,ICT&Future Planning(NRF-2015R1D1A1A02061958 and NRF-2017R1D1A1B04031161)J.-W.P.was supported by a grant from the National Research Found ation of Korea(2017R1AAA1015015)S.H.S.and j.J.H.were supported by the Korea Research Institute of Bioscience and Biotechnology Research Initiative Program(KGM 4571922).
文摘Interleukin-10(IL-10)is the most potent anti-inflammatory cytokine in the body and plays an essential role in determining outcomes of many inflammatory diseases.Cellular metabolism is a critical determinant of immune cell function;however,it is currently unclear whether metabolic processes are specifically involved in IL-10 production.In this study,we aimed to find the central metabolic molecule regulating IL-10 production of macrophages,which are the main producers of IL-10.Transcriptomic analysis identified that metabolic changes were predominantly enriched in Kupffer cells at the early inflammatory phase of a mouse endotoxemia model.Among them,pyruvate dehydrogenase kinase(PDK)-dependent acute glycolysis was negatively involved in IL-10 production.Inhibition or knockdown of PDK selectively increased macrophage IL-10 expression.Mechanistically,PDK inhibition increased IL-10 production via profound phosphorylation of adenosine monophosphate(AMP)-activated protein kinase alpha 1(AMPKα1)by restricting glucose uptake in lipopolysaccharide-stimulated macrophages.AMPKα1 consequently activated p38 mitogen-activated protein kinase,c-Jun N-terminal kinase,and cyclic AMP-responsive element-binding protein to regulate IL-10 production.Our study uncovers a previously unknown regulatory mechanism of IL-10 in activated macrophages involving an immunometabolic function of PDK.
