Abstract
Dendritic cells (DCs) play an important role in innate and adaptive immune responses. In addition to their phagocytic activity, DCs present foreign antigens to naïve T cells and regulate the development of adaptive immune responses. Upon contact with DCs, activated T cells produce large quantities of cytokines such as interferon-gamma (IFN-gamma) and interleukin (IL)-21, which have important immunoregulatory functions. Here, we have analyzed the effect of IL-21 and IFN-gamma on lipopolysaccharide (LPS)-induced maturation and cytokine production of human monocyte-derived DCs. IL-21 and IFN-gamma receptor genes were expressed in high levels in immature DCs. Pretreatment of immature DCs with IL-21 inhibited LPS-stimulated DC maturation and expression of CD86 and human leukocyte antigen class II (HLAII). IL-21 pretreatment also dramatically reduced LPS-stimulated production of tumor necrosis factor alpha, IL-12, CC chemokine ligand 5 (CCL5), and CXC chemokine ligand 10 (CXCL10) but not that of CXCL8. In contrast, IFN-gamma had a positive feedback effect on immature DCs, and it enhanced LPS-induced DC maturation and the production of cytokines. IL-21 weakly induced the expression Toll-like receptor 4 (TLR4) and translation initiation region (TIR) domain-containing adaptor protein (TIRAP) genes, whereas the expression of TIR domain-containing adaptor-inducing IFN-beta (TRIF), myeloid differentiation (MyD88) 88 factor, or TRIF-related adaptor molecule (TRAM) genes remained unchanged. However, IL-21 strongly stimulated the expression of suppressor of cytokine signaling (SOCS)-1 and SOCS-3 genes. SOCS are known to suppress DC functions and interfere with TLR4 signaling. Our results demonstrate that IL-21, a cytokine produced by activated T cells, can directly inhibit the activation and cytokine production of myeloid DCs, providing a negative feedback loop between DCs and T lymphocytes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Communication
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Cells, Cultured / drug effects
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Cells, Cultured / immunology
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Cells, Cultured / metabolism
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Chemokine CCL5
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Chemokines, CC / biosynthesis
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Chemokines, CC / genetics
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Chemokines, CXC / biosynthesis
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Chemokines, CXC / genetics
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Cytokines / biosynthesis*
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Cytokines / genetics
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Dendritic Cells / drug effects*
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Feedback, Physiological
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Gene Expression Profiling
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Gene Expression Regulation / drug effects*
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HLA-DR Antigens / biosynthesis
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Humans
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Interferon gamma Receptor
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Interferon-gamma / pharmacology
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Interleukin-12 / biosynthesis
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Interleukin-12 / genetics
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Interleukin-21 Receptor alpha Subunit
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Interleukins / pharmacology*
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Interleukins / physiology
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Intracellular Signaling Peptides and Proteins / genetics
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Lipopolysaccharides / antagonists & inhibitors
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Lymphocyte Activation
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Macrophages / drug effects
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Macrophages / metabolism
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / genetics
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Receptors, Interferon / biosynthesis
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Receptors, Interferon / genetics
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Receptors, Interleukin / biosynthesis
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Receptors, Interleukin / genetics
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Receptors, Interleukin-1 / biosynthesis
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Receptors, Interleukin-1 / genetics
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Receptors, Interleukin-21
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Recombinant Proteins / pharmacology
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Repressor Proteins / biosynthesis*
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Repressor Proteins / genetics
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins / biosynthesis*
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Suppressor of Cytokine Signaling Proteins / genetics
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism*
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Toll-Like Receptor 4 / biosynthesis
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Toll-Like Receptor 4 / genetics
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / genetics
Substances
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CCL5 protein, human
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Chemokine CCL5
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Chemokines, CC
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Chemokines, CXC
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Cytokines
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HLA-DR Antigens
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IL21R protein, human
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Interleukin-21 Receptor alpha Subunit
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Interleukins
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides
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Membrane Glycoproteins
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RNA, Messenger
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Receptors, Interferon
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Receptors, Interleukin
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Receptors, Interleukin-1
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Receptors, Interleukin-21
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Recombinant Proteins
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Repressor Proteins
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SOCS1 protein, human
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SOCS3 protein, human
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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TIRAP protein, human
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TLR4 protein, human
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Toll-Like Receptor 4
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Tumor Necrosis Factor-alpha
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Interleukin-12
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Interferon-gamma
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interleukin-21