Abstract
DCs orchestrate immune responses to infectious pathogens and disturbances in tissue integrity. Equipped with C-type lectins, DCs can respond to environmental changes in glycosylation. Many C-type lectins are capable of modulating TLR activation, thereby facilitating tailor-made immune reactions. Here, we investigated the signaling properties of the C-type lectin MGL and show that MGL engagement by agonistic antibodies or carbohydrate ligands couples to TLR signal transduction for increased IL-10 and TNF-α secretion by human monocyte-derived DCs. MGL triggering especially synergized with TLR2-induced pathways, leading to elevated IL-10 mRNA levels and enhanced TNF-α mRNA stability. In addition, MGL signaling promoted phosphorylation of the MAPK ERK and the transcription factor CREB. Whereas specific inhibitors of p90RSK blocked the MGL-induced cytokine secretion, AP-1 was not involved. Strikingly, NF-κB was only crucial for the IL-10 response and dispensable for TNF-α production. Together, our results demonstrate that MGL activation of the ERK-p90RSK-CREB axis converges with TLR2-induced pathways, thereby fine-tuning the DC maturation phenotype.
Keywords:
C-type lectin; Tn antigen; dendritic cells; macrophage galactose-type lectin.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylgalactosamine / immunology
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Amino Acid Sequence
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Antigens, Tumor-Associated, Carbohydrate / immunology
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Antigens, Viral / immunology
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Cell Differentiation / drug effects
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Cells, Cultured / immunology
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Cells, Cultured / metabolism
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Cyclic AMP Response Element-Binding Protein / metabolism
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Dendritic Cells / cytology
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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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Enzyme Activation / drug effects
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Humans
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Interleukin-10 / biosynthesis
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Interleukin-10 / genetics
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Interleukin-10 / metabolism*
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Lectins, C-Type / physiology*
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MAP Kinase Signaling System / drug effects
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Macrophages / immunology
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Molecular Sequence Data
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NF-kappa B / metabolism
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Peptide Fragments / immunology
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Phosphorylation / drug effects
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Poliovirus / immunology
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Protein Kinase Inhibitors / pharmacology
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Protein Processing, Post-Translational / drug effects
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RNA Stability / drug effects
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Tetanus Toxin / immunology
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Toll-Like Receptor 2 / biosynthesis
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / physiology*
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Transcription, Genetic / drug effects
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Antigens, Tumor-Associated, Carbohydrate
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Antigens, Viral
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CREB1 protein, human
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Cyclic AMP Response Element-Binding Protein
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IL10 protein, human
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Lectins, C-Type
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MGL lectin, human
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NF-kappa B
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Peptide Fragments
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Protein Kinase Inhibitors
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TLR2 protein, human
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Tetanus Toxin
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Tn antigen
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Toll-Like Receptor 2
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Tumor Necrosis Factor-alpha
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Interleukin-10
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Extracellular Signal-Regulated MAP Kinases
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Acetylgalactosamine