1. Pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages
- Author
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Jung Joo Hong, Seung Hyeok Seok, Juha Song, Yi Rang Na, Jong Wan Park, and Daun Jung
- Subjects
0301 basic medicine ,Adenosine monophosphate ,Lipopolysaccharides ,Pyruvate dehydrogenase kinase ,Kupffer Cells ,p38 mitogen-activated protein kinases ,interleukin-10 ,macrophage ,AcademicSubjects/SCI01180 ,Models, Biological ,p38 Mitogen-Activated Protein Kinases ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,AMP-activated protein kinase ,pyruvate dehydrogenase kinase ,Genetics ,Animals ,Glycolysis ,Phosphorylation ,Protein kinase A ,Cyclic AMP Response Element-Binding Protein ,Molecular Biology ,biology ,Dichloroacetic Acid ,Kinase ,Macrophages ,Adenylate Kinase ,JNK Mitogen-Activated Protein Kinases ,Pyruvate Dehydrogenase Acetyl-Transferring Kinase ,Cell Biology ,General Medicine ,Articles ,Endotoxemia ,Cell biology ,Enzyme Activation ,Interleukin 10 ,030104 developmental biology ,Glucose ,chemistry ,030220 oncology & carcinogenesis ,biology.protein - Abstract
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.
- Published
- 2020