Interferon-gamma switches monocyte differentiation from dendritic cells to macrophages

Blood. 2003 Jan 1;101(1):143-50. doi: 10.1182/blood-2002-04-1164. Epub 2002 Aug 15.

Abstract

Human monocytes differentiate into dendritic cells (DCs) or macrophages according to the nature of environmental signals. Monocytes stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) plus interleukin 4 (IL-4) yield DCs. We tested here whether interferon-gamma (IFN-gamma), a potent activator of macrophages, may modulate monocyte differentiation. Addition of IFN-gamma to IL-4 plus GM-CSF-stimulated monocytes switches their differentiation from DCs to CD14(-)CD64(+) macrophages. IFN-gamma increases macrophage colony-stimulating factor (M-CSF) and IL-6 production by IL-4 plus GM-CSF-stimulated monocytes by acting at the transcriptional level and acts together with IL-4 to up-regulate M-CSF but not IL-6 production. IFN-gamma also increases M-CSF receptor internalization. Results from neutralizing experiments show that both M-CSF and IL-6 are involved in the ability of IFN-gamma to skew monocyte differentiation from DCs to macrophages. Finally, this effect of IFN-gamma is limited to early stages of differentiation. When added to immature DCs, IFN-gamma up-regulates IL-6 but not M-CSF production and does not convert them to macrophages, even in the presence of exogenous M-CSF. In conclusion, IFN-gamma shifts monocyte differentiation to macrophages rather than DCs through autocrine M-CSF and IL-6 production. These data show that IFN-gamma controls the differentiation of antigen-presenting cells and thereby reveals a new mechanism by which IFN-gamma orchestrates the outcome of specific immune responses.

MeSH terms

  • Animals
  • Antigens, CD / analysis
  • Autocrine Communication*
  • Bone Marrow Cells / cytology
  • Cell Culture Techniques / methods
  • Cell Differentiation / drug effects
  • Cytokines / pharmacology
  • Dendritic Cells / cytology*
  • Gene Expression Regulation / drug effects
  • Hematopoietic Stem Cells / drug effects
  • Immunophenotyping
  • Interferon-gamma / pharmacology
  • Interferon-gamma / physiology*
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / pharmacology
  • Macrophage Colony-Stimulating Factor / biosynthesis
  • Macrophage Colony-Stimulating Factor / drug effects
  • Macrophage Colony-Stimulating Factor / pharmacology
  • Macrophages / cytology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Monocytes / cytology*

Substances

  • Antigens, CD
  • Cytokines
  • Interleukin-6
  • Macrophage Colony-Stimulating Factor
  • Interferon-gamma