Role of the p38 MAPK/C/EBPβ Pathway in the Regulation of Phenotype and IL-10 and IL-12 Production by Tolerogenic Bone Marrow-Derived Dendritic Cells

Role of the p38 MAPK/C/EBPβ Pathway in the Regulation of Phenotype and IL-10 and IL-12 Production by Tolerogenic Bone Marrow-Derived Dendritic Cells

Dendritic cells (DCs) play a major role in innate and adaptive immunity and self-immune tolerance. Immunogenic versus tolerogenic DC functions are dictated by their levels of costimulatory molecules and their cytokine expression profile. The transcription factor C/EBPβ regulates the expression of se...

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Bibliographic Details
Published in:Cells (Basel, Switzerland) Vol. 7; no. 12; p. 256
Main Authors: Guindi, Chantal, Cloutier, Alexandre, Gaudreau, Simon, Zerif, Echarki, McDonald, Patrick P, Tatsiy, Olga, Asselin, Claude, Dupuis, Gilles, Gris, Denis, Amrani, And Abdelaziz
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 07-12-2018
MDPI
Subjects:
Adaptive immunity
Antigens
Bone marrow
CCAAT/enhancer-binding protein beta (C/EBPβ)
CD4 antigen
Cell growth
Cell proliferation
Cloning
Cooperation
Costimulator
Cyclic AMP response element-binding protein
Cytokines
Dendritic cells
Deoxyribonucleic acid
DNA
Gene expression
Genotype & phenotype
Granulocyte-macrophage colony-stimulating factor
IL-12
Immunogenicity
Immunological tolerance
Inflammation
Interleukin 10
Interleukin 12
Interleukin 4
Interleukins 10 and 12 (IL-10
Kinases
Lymphocytes
Lymphocytes T
Macrophages
MAP kinase
Phenotypes
Phosphorylation
tolerogenic bone marrow-derived dendritic cells (BMDCs)
Transcription factors
Canada
United States > US
Interleukins 10 and 12 (IL-10
IL-12
tolerogenic bone marrow-derived dendritic cells (BMDCs)
CCAAT/enhancer-binding protein beta (C/EBPβ)
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Summary:Dendritic cells (DCs) play a major role in innate and adaptive immunity and self-immune tolerance. Immunogenic versus tolerogenic DC functions are dictated by their levels of costimulatory molecules and their cytokine expression profile. The transcription factor C/EBPβ regulates the expression of several inflammatory genes in many cell types including macrophages. However, little is known regarding the role of C/EBPβ in tolerogenic versus immunogenic DCs functions. We have previously reported that bone marrow-derived DCs generated with GM-CSF (GM/DCs) acquire the signature of semi-mature tolerogenic IL-10-producing DCs as opposed to immunogenic DCs generated with GM-CSF and IL-4 (IL-4/DCs). Here, we show that tolerogenic GM/DCs exhibit higher levels of phosphorylation and enhanced DNA binding activity of C/EBPβ and CREB than immunogenic IL-4/DCs. We also show that the p38 MAPK/CREB axis and GSK3 play an important role in regulating C/EBPβ phosphorylation and DNA binding activity. Inhibition of p38 MAPK in GM/DCs resulted in a drastic decrease of C/EBPβ and CREB DNA binding activities, a reduction of their IL-10 production and an increase of their IL-12p70 production, a characteristic of immunogenic IL-4/DCs. We also present evidence that GSK3 inhibition in GM/DCs reduced C/EBPβ DNA binding activity and increased expression of costimulatory molecules in GM/DCs and their production of IL-10. Analysis of GM/DCs of C/EBPβ mice showed that C/EBPβ was essential to maintain the semimature phenotype and the production of IL-10 as well as low CD4⁺ T cell proliferation. Our results highlight the importance of the p38MAPK-C/EBPβ pathway in regulating phenotype and function of tolerogenic GM/DCs.
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ISSN:2073-4409
2073-4409
DOI:10.3390/cells7120256