title: MGL signaling augments TLR2-mediated responses for enhanced IL-10 and TNF-α secretion.
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.
authors.affiliation: VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, the Netherlands. s.vanvliet@vumc.nl
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: van Vliet
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bay
authors.forename: Ilona M
authors.initials: IM
authors.lastname: Vuist
authors.forename: Hakan
authors.initials: H
authors.lastname: Kalay
authors.forename: Juan J
authors.initials: JJ
authors.lastname: García-Vallejo
authors.forename: Claude
authors.initials: C
authors.lastname: Leclerc
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Kooyk
mesh_terms: D000116:Acetylgalactosamine / Q000276:immunology; D000595:Amino Acid Sequence; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000276:immunology / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D037181:Lectins, C-Type / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000276:immunology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D017955:Poliovirus / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D013744:Tetanus Toxin / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; D000956:Antigens, Viral; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C508609:IL10 protein, human; D037181:Lectins, C-Type; C506225:MGL lectin, human; D016328:NF-kappa B; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; C495342:TLR2 protein, human; D013744:Tetanus Toxin; C040286:Tn antigen; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D048049:Extracellular Signal-Regulated MAP Kinases; D000116:Acetylgalactosamine
keywords: C-type lectin; Tn antigen; dendritic cells; macrophage galactose-type lectin