Interferon-gamma switches monocyte differentiation from dendritic cells to macrophages.
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.
Delneste
Yves
Y
Department of Biology, Centre d'Immunologie Pierre Fabre, Saint Julien en Genevois, France.
Charbonnier
Peggy
P
Herbault
Nathalie
N
Magistrelli
Giovanni
G
Caron
Gersende
G
Bonnefoy
Jean-Yves
JY
Jeannin
Pascale
P
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D019898:Autocrine Communication; D001854:Bone Marrow Cells / Q000166:cytology; D018929:Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000187:drug effects / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology*
D015703:Antigens, CD; D016207:Cytokines; D015850:Interleukin-6; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma