Abstract
While programmed death-1 (PD-1), a co-inhibitory member of CD28 immunoglobulin superfamily plays negative roles in effector functions of T cells and B cells, little is known about the function of PD-1 expressed on innate immune cells. In this study, we demonstrate that IL-12 production was greatly suppressed in LPS-stimulated RAW264.7 cells upon PD-1 engagement with B7-H1.Fc fusion protein, and was restored in the presence of antagonistic anti-PD-1 mAb. PD-1-mediated suppression of IL-12 production in LPS-stimulated RAW264.7 cells was mediated by inhibition of Janus N-terminal-linked kinase (JNK) signaling pathway, and to a lesser extent, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway through the recruitment of SHP-2 to PD-1 cytoplasmic tail. B7-H1.Fc-mediated PD-1 engagement also downregulates the expression of co-stimulatory molecules such as CD80, CD86, MHC class I and II proteins in LPS-stimulated RAW264.7 cells. Furthermore, the endocytic activity is enhanced but the allostimulatory capacity is suppressed in LPS-treated RAW264.7 cells upon PD-1 engagement. Taken together, our results reveal a novel function of macrophage PD-1 in the negative regulation of IL-12 synthesis and differentiation into dendritic cell-like cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Blocking
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Antigen Presentation / drug effects
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Antigen Presentation / immunology
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Antigens, Differentiation / biosynthesis
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Antigens, Differentiation / genetics
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B7-1 Antigen / metabolism
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B7-1 Antigen / pharmacology
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B7-H1 Antigen
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Cell Differentiation / drug effects
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Cell Differentiation / immunology
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Cell Line
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Down-Regulation
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Endocytosis / drug effects
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Interleukin-12 / biosynthesis*
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Interleukin-12 / genetics
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Lipopolysaccharides / pharmacology
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Lymphocyte Culture Test, Mixed
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MAP Kinase Kinase 4 / metabolism
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / metabolism*
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Macrophages / pathology
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Membrane Glycoproteins / metabolism
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Membrane Glycoproteins / pharmacology
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Mice
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Peptides / metabolism
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Peptides / pharmacology
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Programmed Cell Death 1 Receptor
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Receptors, Immunologic / immunology
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Receptors, Immunologic / metabolism*
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Recombinant Fusion Proteins / metabolism
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Recombinant Fusion Proteins / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / immunology
Substances
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Antibodies, Blocking
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Antigens, Differentiation
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B7-1 Antigen
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B7-H1 Antigen
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Cd274 protein, mouse
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Lipopolysaccharides
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Membrane Glycoproteins
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Pdcd1 protein, mouse
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Peptides
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Programmed Cell Death 1 Receptor
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Receptors, Immunologic
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Recombinant Fusion Proteins
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Interleukin-12
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MAP Kinase Kinase 4