Article: BET bromodomain inhibition reduces maturation and enhances tolerogenic properties of human and mouse dendritic cells
Molecular Immunology. 2016 Nov., v. 79
2016
Abstract: 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 ... ...
| Abstract | 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. |
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| Keywords | T-lymphocytes ; acetylation ; bone marrow ; chemokines ; colitis ; dendritic cells ; genes ; histones ; humans ; inflammation ; interleukin-10 ; interleukin-12 ; interleukin-6 ; macrophages ; mice ; models ; monocytes ; ovalbumin ; phenotype ; secretion |
| Language | English |
| Dates of publication | 2016-11 |
| Size | p. 66-76. |
| Publishing place | Elsevier Ltd |
| Document type | Article |
| ZDB-ID | 424427-8 |
| ISSN | 1872-9142 ; 0161-5890 |
| ISSN (online) | 1872-9142 |
| ISSN | 0161-5890 |
| DOI | 10.1016/j.molimm.2016.09.010 |
| Database | NAL-Catalogue (AGRICOLA) |
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