title: Differential role of NF-κB, ERK1/2 and AP-1 in modulating the immunoregulatory functions of bone marrow-derived dendritic cells from NOD mice.
abstract: Tolerogenic dendritic cells represent a promising immunotherapy in autoimmunity. However, the molecular mechanisms that drive tolerogenic DCs functions are not well understood. We used GM-CSF or GM-CSF+IL-4 to generate tolerogenic (GM/DCs) and immunogenic (IL-4/DCs) BMDCs from NOD mice, respectively. GM/DCs were resistant to maturation, produced large amounts of IL-10 but not IL-12p70. GM/DCs displayed a reduced capacity to activate diabetogenic CD8(+) T-cells and were efficient to induce Tregs expansion and conversion. LPS stimulation triggered ERK1/2 activation that was sustained in GM/DCs but not in IL-4/DCs. ERK1/2 and AP-1 were involved in IL-10 production in GM/DCs but not in their resistance to maturation. Supershift analysis showed that NF-κB DNA binding complex contains p52 and p65 in GM/DCs, whereas it contains p52, p65 and RelB in IL-4/DCs. ChIP experiments revealed that p65 was recruited to IL-10 promoter following LPS stimulation of GM/DCs whereas its binding to IL-12p35 promoter was abolished. Our results suggest that immunoregulatory functions of GM/DCs are differentially regulated by ERK1/2, AP-1 and NF-κB pathways.
authors: Immunology Division, and Centre de Recherche Clinique Etienne LeBel, University of Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4.
authors: Chantal
authors: C
authors: Guindi
authors: Michaël
authors: M
authors: Ménard
authors: Alexandre
authors: A
authors: Cloutier
authors: Simon
authors: S
authors: Gaudreau
authors: Gilles
authors: G
authors: Besin
authors: Pierre
authors: P
authors: Larivée
authors: Patrick P
authors: PP
authors: McDonald
authors: Gilles
authors: G
authors: Dupuis
authors: Abdelaziz
authors: A
authors: Amrani
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D048708:Cell Growth Processes / Q000276:immunology; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D053765:Interleukin-12 Subunit p35 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016328:NF-kappa B / Q000276:immunology*; D052003:NF-kappa B p52 Subunit / Q000276:immunology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000276:immunology*; D051996:Transcription Factor RelA / Q000276:immunology; D051841:Transcription Factor RelB / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; D053765:Interleukin-12 Subunit p35; D008070:Lipopolysaccharides; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; C498144:Rela protein, mouse; C497594:Relb protein, mouse; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D016753:Interleukin-10; D051841:Transcription Factor RelB; D018664:Interleukin-12; D015847:Interleukin-4