Journal
JOURNAL OF IMMUNOLOGY
Volume 197, Issue 10, Pages 4101-4109Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1600745
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Funding
- Basic Science Research Program through the National Research Foundation of Korea - Ministry of Science, ICT and Future Planning [NRF-2014R1A1A1008012, 2015R1D1A1A02061958]
- Promising-Pioneering Researcher Program through Seoul National University
- Seoul National University Hospital [0320150050]
- National Research Foundation of Korea [2015R1D1A1A02061958] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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GM-CSF induces proinflammatory macrophages, but the underlying mechanisms have not been studied thus far. In this study, we investigated the mechanisms of how GM-CSF induces inflammatory macrophages. First, we observed that GM-CSF increased the extent of LPS-induced acute glycolysis in murine bone marrow-derived macrophages. This directly correlates with an inflammatory phenotype because glycolysis inhibition by 2-deoxyglucose abolished GM-CSF-mediated increase of TNF-alpha,IL-1 beta, IL-6, and IL-12p70 synthesis upon LPS stimulation. Increased glycolytic capacity is due to de novo synthesis of glucose transporter ( GLUT)-1,-3, and-4, as well as c-myc. Mean while, GM-CSF increased 3-hydroxy-3-methyl-glutaryl-CoA reductase, which is the rate-limiting enzyme of the mevalonate pathway. Inhibition of acute glycolysis or 3-hydroxy-3-methyl-glutaryl-CoA reductase abrogated the inflammatory effects of GM-CSF priming in macrophages. Finally, mice with inflamed colons exposed to dextran sodium sulfate containing GLUT-1(high) macrophages led to massive uptake of [F-18]-fluorodeoxyglucose, but GM-CSF neutralization reduced the positron-emission tomography signal in the intestine and also decreased GLUT-1 expression in colonic macrophages. Collectively, our results reveal glycolysis and lipid metabolism created by GM-CSF as the underlying metabolic constructs for the function of inflammatory macrophages.
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