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Pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages
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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493030/ https://www.ncbi.nlm.nih.gov/pubmed/31900478 http://dx.doi.org/10.1093/jmcb/mjz113 |
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author | Na, Yi Rang Jung, Daun Song, Juha Park, Jong-Wan Hong, Jung Joo Seok, Seung Hyeok |
author_facet | Na, Yi Rang Jung, Daun Song, Juha Park, Jong-Wan Hong, Jung Joo Seok, Seung Hyeok |
author_sort | Na, Yi Rang |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7493030 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-74930302020-09-21 Pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages Na, Yi Rang Jung, Daun Song, Juha Park, Jong-Wan Hong, Jung Joo Seok, Seung Hyeok J Mol Cell Biol Articles 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. Oxford University Press 2020-01-03 /pmc/articles/PMC7493030/ /pubmed/31900478 http://dx.doi.org/10.1093/jmcb/mjz113 Text en © The Author(s) (2020). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Articles Na, Yi Rang Jung, Daun Song, Juha Park, Jong-Wan Hong, Jung Joo Seok, Seung Hyeok Pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages |
title | Pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages |
title_full | Pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages |
title_fullStr | Pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages |
title_full_unstemmed | Pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages |
title_short | Pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages |
title_sort | pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493030/ https://www.ncbi.nlm.nih.gov/pubmed/31900478 http://dx.doi.org/10.1093/jmcb/mjz113 |
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