GM-CSF priming drives bone marrow-derived macrophages to a pro-inflammatory pattern and downmodulates PGE2 in response to TLR2 ligands

PLoS One. 2012;7(7):e40523. doi: 10.1371/journal.pone.0040523. Epub 2012 Jul 13.


In response to pathogen recognition by Toll-like receptors (TLRs) on their cell surface, macrophages release lipid mediators and cytokines that are widely distributed throughout the body and play essential roles in host responses. Granulocyte macrophage colony-stimulating factor (GM-CSF) is important for the immune response during infections to improve the clearance of microorganisms. In this study, we examined the release of mediators in response to TLR2 ligands by bone marrow-derived macrophages (BMDMs) primed with GM-CSF. We demonstrated that when stimulated with TLR2 ligands, non-primed BMDMs preferentially produced PGE(2) in greater amounts than LTB(4). However, GM-CSF priming shifted the release of lipid mediators by BMDMs, resulting in a significant decrease of PGE(2) production in response to the same stimuli. The decrease of PGE(2) production from primed BMDMs was accompanied by a decrease in PGE-synthase mRNA expression and an increase in TNF-α and nitric oxide (NO) production. Moreover, some GM-CSF effects were potentiated by the addition of IFN-γ. Using a variety of TLR2 ligands, we established that PGE(2) release by GM-CSF-primed BMDMs was dependent on TLR2 co-receptors (TLR1, TLR6), CD14, MyD88 and the nuclear translocation of NFκB but was not dependent on peroxisome proliferator-activated receptor-γ (PPAR-γ) activation. Indeed, GM-CSF priming enhanced TLR2, TLR4 and MyD88 mRNA expression and phospho-IκBα formation. These findings demonstrate that GM-CSF drives BMDMs to present a profile relevant to the host during infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Bacteria / metabolism
  • Dinoprostone / metabolism*
  • Down-Regulation / drug effects*
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology*
  • Inflammation / metabolism
  • Inflammation / pathology*
  • Interferon-gamma / pharmacology
  • Interleukin-10 / biosynthesis
  • Leukotriene B4 / metabolism
  • Ligands
  • Lipid Metabolism
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Differentiation Factor 88 / metabolism
  • NF-kappa B / metabolism
  • Nitric Oxide / metabolism
  • PPAR gamma / metabolism
  • Protein Transport / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Toll-Like Receptor 2 / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism


  • Adaptor Proteins, Signal Transducing
  • Ligands
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • PPAR gamma
  • RNA, Messenger
  • Toll-Like Receptor 2
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Leukotriene B4
  • Nitric Oxide
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Dinoprostone