Abstract
Growing evidence has demonstrated that members of TNF superfamily transduce signals after engagement with their receptors. TNF-related activation-induced cytokine (TRANCE), a member of TNF superfamily, is preferentially expressed on the surface of activated CD4(+) Th1 cells. The soluble receptor activator of NF-kappaB (RANK).Fc fusion protein suppresses IFN-gamma secretion by activated Th1 cells, but does not affect IL-4 secretion by Th2 cells. The suppressive effect on IFN-gamma secretion is observed when Th1 cells are activated by APCs, but not by immobilized anti-TCR beta mAb. In contrast, immobilized RANK.Fc fusion protein augments IFN-gamma secretion by Th1 cells, indicating the occurrence of reverse signaling through TRANCE during T cell/APC interaction. The enhanced secretion of IFN-gamma mediated via TRANCE correlates with the activation of p38 mitogen-activated protein kinase and is blocked by SB203580, a p38 mitogen-activated protein kinase-specific inhibitor. Thus, in addition to its role in activating dendritic cells by binding to the receptor RANK, TRANCE itself can signal the augmentation of IFN-gamma secretion via a p38-dependent pathway, and this provides yet another example of reverse signaling by a member of TNF superfamily.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / biosynthesis
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Carrier Proteins / physiology*
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cytokines / biosynthesis
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Cytokines / genetics
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Cytokines / metabolism
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Cytokines / physiology*
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Enzyme Activation / genetics
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Enzyme Activation / immunology
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Enzyme Inhibitors / pharmacology
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Humans
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / metabolism*
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Lymphocyte Activation* / genetics
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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Membrane Glycoproteins / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / metabolism
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / metabolism
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Receptors, Tumor Necrosis Factor / physiology
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Recombinant Fusion Proteins / immunology
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Recombinant Fusion Proteins / metabolism
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Recombinant Fusion Proteins / pharmacology
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Th1 Cells / cytology
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Th1 Cells / immunology
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Th1 Cells / metabolism*
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Th2 Cells / cytology
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Th2 Cells / metabolism
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Up-Regulation / drug effects
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Up-Regulation / genetics
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Up-Regulation / immunology
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p38 Mitogen-Activated Protein Kinases
Substances
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Carrier Proteins
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Cytokines
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Enzyme Inhibitors
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Membrane Glycoproteins
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NF-kappa B
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Tumor Necrosis Factor
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Recombinant Fusion Proteins
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TNFRSF11A protein, human
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TNFSF11 protein, human
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Tnfrsf11a protein, mouse
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Tnfsf11 protein, mouse
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Interferon-gamma
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases