BET bromodomain inhibition reduces maturation and enhances tolerogenic properties of human and mouse dendritic cells
| Autor: | Rab K. Prinjha, Paul P. Tak, Wouter J. de Jonge, Francisca W. Hilbers, Kris A. Reedquist, David F. Tough, Pawel A. Kabala, Matthew J Bell, Eleonora Reginato, Chris Patten, Ronald Schilderink, Inmaculada Rioja |
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| Přispěvatelé: | Graduate School, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Tytgat Institute for Liver and Intestinal Research, AII - Amsterdam institute for Infection and Immunity, Experimental Immunology, Clinical Immunology and Rheumatology, Gastroenterology and Hepatology |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Chemokine T cell Blotting Western Immunology Inflammation Lymphocyte Activation Heterocyclic Compounds 4 or More Rings Polymerase Chain Reaction T-Lymphocytes Regulatory 03 medical and health sciences Mice medicine Immune Tolerance Animals Humans Secretion Molecular Biology Mice Knockout biology FOXP3 Dendritic cell Dendritic Cells Colitis Flow Cytometry Coculture Techniques Bromodomain Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure biology.protein Cancer research Cytokines Cytokine secretion medicine.symptom |
| Zdroj: | Molecular immunology, 79, 66-76. Elsevier Limited |
| ISSN: | 0161-5890 |
| DOI: | 10.1016/j.molimm.2016.09.010 |
| Popis: | Transcription of inflammatory genes is tightly regulated by acetylation and deacetylation of histone tails. An inhibitor of the acetylated-lysine reader bromodomain and extra-terminal domain (BET) proteins, I-BET151, is known to counteract the induction of expression of inflammatory genes in macrophages. We have investigated the effects of I-BET151 on dendritic cell function, including expression of co-stimulatory molecules and cytokines, and capacity for T cell activation. Treatment of mouse bone marrow derived dendritic cells (BMDC) and human monocyte derived DCs (mdDC) with I-BET151 reduced LPS-induced expression of co-stimulatory molecules, as well as the production of multiple cyokines and chemokines. Most strikingly, secretion of IL-6, IL-12 and IL-10 was significantly reduced to 89.7%, 99.9% and 98.6% respectively of that produced by control cells. I-BET151-treated mdDC showed a reduced ability to stimulate proliferation of autologous Revaxis-specific T cells. Moreover, while I-BET151 treatment of BMDC did not affect their ability to polarise ovalbumin specific CD4(+) CD62L(+) naive T cells towards Th1, Th2, or Th17 phenotypes, an increase in Foxp3 expressing Tregs secreting higher IL-10 levels was observed. Suppression assays demonstrated that Tregs generated in response to I-BET151-treated BMDC displayed anti-proliferative capacity. Finally, evidence that I-BET151 treatment can ameliorate inflammation in vivo in a T cell dependent colitis model is shown. Overall, these results demonstrate marked effects of BET inhibition on DC maturation, reducing their capacity for pro-inflammatory cytokine secretion and T cell activation and enhancing the potential of DC to induce Foxp3 expressing Treg with suppressive properties |
| Databáze: | OpenAIRE |
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