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GM-CSF Enhances Macrophage Glycolytic Activity In Vitro and Improves Detection of Inflammation In Vivo.



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Singh, Parmanand 
González-Ramos, Silvia 
Mojena, Marina 
Rosales-Mendoza, César Eduardo 
Emami, Hamed 


UNLABELLED: (18)F-FDG accumulates in glycolytically active tissues and is known to concentrate in tissues that are rich in activated macrophages. In this study, we tested the hypotheses that human granulocyte-macrophage colony-stimulating factor (GM-CSF), a clinically used cytokine, increases macrophage glycolysis and deoxyglucose uptake in vitro and acutely enhances (18)F-FDG uptake within inflamed tissues such as atherosclerotic plaques in vivo. METHODS: In vitro experiments were conducted on human macrophages whereby inflammatory activation and uptake of radiolabeled 2-deoxyglucose was assessed before and after GM-CSF exposure. In vivo studies were performed on mice and New Zealand White rabbits to assess the effect of GM-CSF on (18)F-FDG uptake in normal versus inflamed arteries, using PET. RESULTS: Incubation of human macrophages with GM-CSF resulted in increased glycolysis and increased 2-deoxyglucose uptake (P < 0.05). This effect was attenuated by neutralizing antibodies against tumor necrosis factor-α or after silencing or inhibition of 6-phosphofructo-2-kinase. In vivo, in mice and in rabbits, intravenous GM-CSF administration resulted in a 70% and 73% increase (P < 0.01 for both), respectively, in arterial (18)F-FDG uptake in atherosclerotic animals but not in nonatherosclerotic controls. Histopathologic analysis demonstrated a significant correlation between in vivo (18)F-FDG uptake and macrophage staining (R = 0.75, P < 0.01). CONCLUSION: GM-CSF substantially augments glycolytic flux in vitro (via a mechanism dependent on ubiquitous type 6-phosphofructo-2-kinase and tumor necrosis factor-α) and increases (18)F-FDG uptake within inflamed atheroma in vivo. These findings demonstrate that GM-CSF can be used to enhance detection of inflammation. Further studies should explore the role of GM-CSF stimulation to enhance the detection of inflammatory foci in other disease states.



18F-FDG-PET, GM-CSF, glycolysis, inflammation, macrophage, Animals, Arteritis, Cells, Cultured, Fluorodeoxyglucose F18, Glycolysis, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Image Enhancement, Macrophages, Male, Mice, Positron-Emission Tomography, Rabbits, Radiopharmaceuticals, Reproducibility of Results, Sensitivity and Specificity

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J Nucl Med

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Society of Nuclear Medicine
British Heart Foundation (None)
British Heart Foundation (None)
JHFR is part-supported by the Cambridge Biomedical Research Centre, the British Heart Foundation and HEFCE. ZAF is supported by NIH/NHLBI R01 HL071021, R01 HL078667; NIH/NBIB R01 EB009638 and NIH/NHLBI Program of Excellence in Nanotechnology (PEN) Award, Contract #HHSN268201000045C. PS was supported by a grant from the NHLBI (5T32 HL076136), and is funded by The Marfan Foundation. LB was supported by SAF2014-52492R, IPT2012-1331-060000 from MINECO; RD12/0042/0019 and Ciberehd are funded by the Instituto de Salud Carlos III, and S2010/BMD-2378 from Comunidad de Madrid, and Dr. A Tawakol is supported by NIH/NHLBI R01 HL122177.