Differential role of NF-¦ÊB, ERK1/2 and AP-1 in modulating the immunoregulatory functions of bone marrow-derived dendritic cells from NOD mice

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• 作者：Chantal Guindi¹ ; Michaë ; l Mé ; nard¹ ; Alexandre Cloutier ; Simon Gaudreau ; Gilles Besin ; Pierre Larivé ; e ; Patrick P. McDonald ; Gilles Dupuis ; Abdelaziz Amrani ; ^{Abdelaziz.Amrani@USherbrooke.ca}
• 关键词：Dendritic cells ; Tolerogenic ; Type 1 diabetes ; Cytokines
• 刊名：Cellular Immunology
• 出版年：2012
• 出版时间：2012
• 年：2012
• 卷：272
• 期：2
• 页码：259-268
• 全文大小：903 K

文摘

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-¦ÊB 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-¦ÊB pathways.