BET bromodomain inhibition reduces maturation and enhances tolerogenic properties of human and mouse dendritic cells

Mol Immunol. 2016 Nov;79:66-76. doi: 10.1016/j.molimm.2016.09.010. Epub 2016 Oct 3.

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.

Keywords: Bromodomain; Dendritic cells; Epigenetics; Immune suppression; Tolerance.

MeSH terms

  • Animals
  • Blotting, Western
  • Coculture Techniques
  • Colitis / immunology
  • Cytokines / biosynthesis
  • Cytokines / drug effects
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Disease Models, Animal
  • Flow Cytometry
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Humans
  • Immune Tolerance / drug effects
  • Immune Tolerance / immunology*
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Polymerase Chain Reaction
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • Cytokines
  • GSK1210151A
  • Heterocyclic Compounds, 4 or More Rings