MGL signaling augments TLR2-mediated responses for enhanced IL-10 and TNF-α secretion

J Leukoc Biol. 2013 Aug;94(2):315-23. doi: 10.1189/jlb.1012520. Epub 2013 Jun 6.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylgalactosamine / immunology
  • Amino Acid Sequence
  • Antigens, Tumor-Associated, Carbohydrate / immunology
  • Antigens, Viral / immunology
  • Cell Differentiation / drug effects
  • Cells, Cultured / immunology
  • Cells, Cultured / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Dendritic Cells / cytology
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Interleukin-10 / biosynthesis
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism*
  • Lectins, C-Type / physiology*
  • MAP Kinase Signaling System / drug effects
  • Macrophages / immunology
  • Molecular Sequence Data
  • NF-kappa B / metabolism
  • Peptide Fragments / immunology
  • Phosphorylation / drug effects
  • Poliovirus / immunology
  • Protein Kinase Inhibitors / pharmacology
  • Protein Processing, Post-Translational / drug effects
  • RNA Stability / drug effects
  • Tetanus Toxin / immunology
  • Toll-Like Receptor 2 / biosynthesis
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / physiology*
  • Transcription, Genetic / drug effects
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Antigens, Tumor-Associated, Carbohydrate
  • Antigens, Viral
  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • IL10 protein, human
  • Lectins, C-Type
  • MGL lectin, human
  • NF-kappa B
  • Peptide Fragments
  • Protein Kinase Inhibitors
  • TLR2 protein, human
  • Tetanus Toxin
  • Tn antigen
  • Toll-Like Receptor 2
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Extracellular Signal-Regulated MAP Kinases
  • Acetylgalactosamine