Publication Date:
2013-03-29
Description:
Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1beta but not tumour-necrosis factor-alpha in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (gamma-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1alpha, an effect that is inhibited by 2-deoxyglucose, with interleukin-1beta as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1beta production during inflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031686/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031686/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tannahill, G M -- Curtis, A M -- Adamik, J -- Palsson-McDermott, E M -- McGettrick, A F -- Goel, G -- Frezza, C -- Bernard, N J -- Kelly, B -- Foley, N H -- Zheng, L -- Gardet, A -- Tong, Z -- Jany, S S -- Corr, S C -- Haneklaus, M -- Caffrey, B E -- Pierce, K -- Walmsley, S -- Beasley, F C -- Cummins, E -- Nizet, V -- Whyte, M -- Taylor, C T -- Lin, H -- Masters, S L -- Gottlieb, E -- Kelly, V P -- Clish, C -- Auron, P E -- Xavier, R J -- O'Neill, L A J -- 098516/Wellcome Trust/United Kingdom -- R01 AI093451/AI/NIAID NIH HHS/ -- R56 AI090863/AI/NIAID NIH HHS/ -- U54 AI057153/AI/NIAID NIH HHS/ -- Wellcome Trust/United Kingdom -- England -- Nature. 2013 Apr 11;496(7444):238-42. doi: 10.1038/nature11986. Epub 2013 Mar 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23535595" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Bone Marrow Cells/cytology
;
Citric Acid Cycle/drug effects
;
Deoxyglucose/pharmacology
;
Down-Regulation/drug effects
;
Genes, Mitochondrial/drug effects/genetics
;
Glutamine/metabolism
;
Glycolysis/drug effects/genetics
;
Humans
;
Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
;
Immunity, Innate/drug effects
;
Inflammation/metabolism
;
Interleukin-1beta/*biosynthesis/genetics
;
Lipopolysaccharides/pharmacology
;
Macrophages/cytology/drug effects/metabolism
;
Mice
;
*Signal Transduction
;
Succinic Acid/*metabolism
;
Up-Regulation/drug effects
;
gamma-Aminobutyric Acid/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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