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Pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages.

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.

SUBMITTER: Na YR

PROVIDER: S-EPMC7493030 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype.

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Asp295 stabilizes the active-site loop structure of pyruvate dehydrogenase, facilitating phosphorylation of ser292 by pyruvate dehydrogenase-kinase.

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Human Cytomegalovirus-Induced Interleukin-10 Production Promotes the Proliferation of Mycobacterium massiliense in Macrophages

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2020-09-08 | GSE141236 | GEO

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