title: Identification of a non-growth factor role for GM-CSF in advanced atherosclerosis: promotion of macrophage apoptosis and plaque necrosis through IL-23 signaling.
abstract: BACKGROUND
  Granulocyte macrophage colony-stimulating factor (GM-CSF, Csf2) is a growth factor for myeloid-lineage cells that has been implicated in the pathogenesis of atherosclerosis and other chronic inflammatory diseases. However, the role of GM-CSF in advanced atherosclerotic plaque progression, the process that gives rise to clinically dangerous plaques, is unknown.
  
  
  OBJECTIVE
  To understand the role of GM-CSF in advanced atherosclerotic plaque progression.
  
  
  RESULTS
  Ldlr(-/-) mice and Csf2(-/-)Ldlr(-/-) mice were fed a Western-type diet for 12 weeks, and then parameters of advanced plaque progression in the aortic root were quantified. Lesions from the GM-CSF-deficient mice showed a substantial decrease in 2 key hallmarks of advanced atherosclerosis, lesional macrophage apoptosis and plaque necrosis, which indicates that GM-CSF promotes plaque progression. Based on a combination of in vitro and in vivo studies, we show that the mechanism involves GM-CSF-mediated production of interleukin-23, which increases apoptosis susceptibility in macrophages by promoting proteasomal degradation of the cell survival protein Bcl-2 (B-cell lymphoma 2) and by increasing oxidative stress.
  
  
  CONCLUSIONS
  In low-density lipoprotein-driven atherosclerosis in mice, GM-CSF promotes advanced plaque progression by increasing macrophage apoptosis susceptibility. This action of GM-CSF is mediated by its interleukin-23-inducing activity rather than its role as a growth factor.
authors.affiliation: From the Departments of Medicine (M.S., I.T.), Pathology and Cell Biology (I.T.), and Physiology and Cellular Biophysics (I.T.), Columbia University, New York, NY; and Department of Pathology, Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (E.T.).
authors.forename: Manikandan
authors.initials: M
authors.lastname: Subramanian
authors.affiliation: From the Departments of Medicine (M.S., I.T.), Pathology and Cell Biology (I.T.), and Physiology and Cellular Biophysics (I.T.), Columbia University, New York, NY; and Department of Pathology, Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (E.T.).
authors.forename: Edward
authors.initials: E
authors.lastname: Thorp
authors.affiliation: From the Departments of Medicine (M.S., I.T.), Pathology and Cell Biology (I.T.), and Physiology and Cellular Biophysics (I.T.), Columbia University, New York, NY; and Department of Pathology, Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (E.T.). iat1@columbia.edu.
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency*; D036341:Intercellular Signaling Peptides and Proteins; D053759:Interleukin-23 / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis / Q000378:metabolism / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D053759:Interleukin-23; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: apoptosis; atherosclerosis; cytokines; granulocyte macrophage colony-stimulating factor; intercellular signaling peptides and proteins; interleukin-23