title: GM-CSF Enhances Macrophage Glycolytic Activity In Vitro and Improves Detection of Inflammation In Vivo.
abstract: (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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Cardiology Division, New York Presbyterian Hospital, Weill Cornell Medical College, New York, New York.
authors.forename: Parmanand
authors.initials: P
authors.lastname: Singh
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols," CSIC-UAM, Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: González-Ramos
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols," CSIC-UAM, Madrid, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Mojena
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols," CSIC-UAM, Madrid, Spain Departamento de Bioquímica y Medicina Molecular, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México.
authors.forename: César Eduardo
authors.initials: CE
authors.lastname: Rosales-Mendoza
authors.affiliation: Cardiac MR PET CT Program, Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Hamed
authors.initials: H
authors.lastname: Emami
authors.affiliation: Cardiac MR PET CT Program, Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Swanson
authors.affiliation: Cardiac MR PET CT Program, Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Alex
authors.initials: A
authors.lastname: Morss
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Zahi A
authors.initials: ZA
authors.lastname: Fayad
authors.affiliation: Division of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: James H F
authors.initials: JH
authors.lastname: Rudd
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Gelfand
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols," CSIC-UAM, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Paz-García
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols," CSIC-UAM, Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín-Sanz
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols," CSIC-UAM, Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
authors.affiliation: Cardiac MR PET CT Program, Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts lbosca@iib.uam.es.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Tawakol
mesh_terms: D000818:Animals; D001167:Arteritis / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002478:Cells, Cultured; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D006019:Glycolysis / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D006801:Humans; D007089:Image Enhancement / Q000379:methods; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011817:Rabbits; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: 18F-FDG-PET; GM-CSF; glycolysis; inflammation; macrophage