Interferon-γ switches monocyte differentiation from dendritic cells to macrophages

　

　

 

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-γ (IFN-γ), a potent activator of macrophages, may modulate monocyte differentiation. Addition of IFN-γ to IL-4 plus GM-CSF–stimulated monocytes switches their differentiation from DCs to CD14−CD64+ macrophages. IFN-γ 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-γ 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-γ to skew monocyte differentiation from DCs to macrophages. Finally, this effect of IFN-γ is limited to early stages of differentiation. When added to immature DCs, IFN-γ 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-γ shifts monocyte differentiation to macrophages rather than DCs through autocrine M-CSF and IL-6 production. These data show that IFN-γ controls the differentiation of antigen-presenting cells and thereby reveals a new mechanism by which IFN-γ orchestrates the outcome of specific immune responses.

 

Introduction

 

Peripheral blood monocytes can differentiate into dendritic cells (DCs) or macrophages depending on environmental factors encountered during their migration from blood to peripheral tissues.1-4 Transendothelial trafficking5 and culture in the presence of serum from systemic lupus erythematosus (through the presence of interferon α [IFN-α]) induce monocyte differentiation into immature DCs.6 On contact with interleukin 4 (IL-4) plus granulocyte-macrophage colony-stimulating factor (GM-CSF; cytokines that could be produced by tissue mast cells), monocytes also differentiate into immature DCs.2-4Addition of transforming growth factor β (TGF-β) or exposition of monocytes to GM-CSF plus IL-15 led to DCs with features of Langerhans cells.7 8 In contrast, macrophage colony-stimulating factor (M-CSF) is a potent macrophage differentiation factor.1 IL-69 10 and IL-1011also shift monocyte differentiation from DCs to macrophages. Tumor cells produce IL-6 and M-CSF that shift the differentiation of CD34+ progenitors from DCs to macrophages.9Fibroblasts, via IL-6 production, up-regulate functional M-CSF receptor (CD115) expression and autocrine M-CSF consummation by monocytes, thereby switching their differentiation from DCs to macrophages.10

 

DCs are the most potent antigen-presenting cells (APCs).12 In the periphery, immature DCs capture antigens and, on contact with stress factors (such as microbial components), migrate to the lymphoid organs and undergo a maturation process. They express high levels of costimulatory and accessory molecules, up-regulate major histocompatibility complex (MHC) class I and II molecules, and neoexpress CD83. In the lymph nodes, mature DCs prime naive antigen-specific T cells.12 In contrast to DCs, macrophages are effector cells that produce various mediators and have evolved to ingest as many pathogens as possible. Although they present antigens, macrophages are less efficient than DCs and unable to prime naive T cells.13

 

IFN-γ, released during early and late stages of the immune response by natural killer (NK) cells and activated T cells, respectively, regulates several aspects of the immune response.14 In addition to direct antiviral activity, IFN-γ orchestrates leukocyte-endothelium interaction14and plays a crucial role in vivo in “cancer immunosurveillance.”15 IFN-γ is a potent activator of macrophages. On contact with IFN-γ, monocyte-macrophages undergo biochemical and morphologic modifications that allow them to perform their functional activities.16 INF-γ stimulates macrophage antimicrobial and tumoricidal activities and accessory cell functions and modulates proteasome gene expression.16IFN-γ also acts on uncommitted myeloid immature DCs to polarize them into TH1 cell–promoting effector cells that produce high levels of IL-12 on stimulation.17 We tested here whether IFN-γ could be involved in monocyte differentiation and report that IFN-γ switches monocyte differentiation from DCs to macrophages, at least partly via an autocrine production of M-CSF and IL-6.

　

Yves Delneste, Peggy Charbonnier, Nathalie Herbault, Giovanni Magistrelli, Gersende Caron, Jean-Yves Bonnefoy and Pascale Jeannin

Blood 2003 101:143-150; doi: https://doi.org/10.1182/blood-2002-04-1164

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http://www.bloodjournal.org/content/101/1/143?sso-checked=true