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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.