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

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.

Ameliorative effect of a quinazoline-based bromodomain inhibitor, CN210, on experimentally-induced Crohn’s disease-like murine ileitis via inhibition of inflammatory cytokine expression

“…In recent years, BET inhibitors have attracted attention as a novel class of drug candidates not only for cancer but also for various inflammatory diseases [13, 14]. Several studies demonstrated that BET inhibitors were effective in the models of arthritis, vascular inflammation, acute pancreatitis, hepatic fibrosis and renal damage [23, 29–32], as well as in T cell-transfer colitis models [21, 22]. In the present study, we demonstrated that a novel quinazoline-based bromodomain inhibitor, CN210, inhibited CBP and p300 in addition to BET proteins and that CN210 potently attenuated indomethacin-induced CD-like ileitis in mice.…”

“…Furthermore, it is known that BET proteins regulate gene transcriptions during the differentiation of naïve CD4 + cells to mature helper-T cells, and that BET inhibitors, such as JQ1, attenuated the differentiation of Th1, Th2, and Th17 cells [35, 36]. BET inhibitors have also reported to suppress inflammatory cytokine production and T-cell activation via inhibition of dendritic cell maturation and promotion of regulatory T-cell differentiation [22].…”

Epigenetics, DNA Organization, and Inflammatory Bowel Disease

“…Treatment with I-BET151 reduces maturation marker and pro-inflammatory cytokine expression in dendritic cells and inhibits mature dendritic cell–mediated, antigen-dependent proliferation of naïve CD4 + T cells. 91 Dendritic cells treated with I-BET151 remain immature, and this led to increased generation of immunosuppressive Foxp3 + Tregs in vitro. Disappointingly, mice (Rag1 -/- mice transferred with CD45RB high sorted T cells) experiencing chronic colitis due to impaired Treg function displayed only modest improvement in disease symptoms when treated with I-BET151.…”

“…Disappointingly, mice (Rag1 -/- mice transferred with CD45RB high sorted T cells) experiencing chronic colitis due to impaired Treg function displayed only modest improvement in disease symptoms when treated with I-BET151. 91 One explanation could be timing; I-BET151 administration in these mice occurred after colitis symptoms appeared and after priming of naïve T cells by dendritic cells had already occurred. Since earlier experiments negatively implicated I-BET151 in dendritic cell maturation and T cell activation, treatment with I-BET151 at an earlier stage could lead to higher Treg levels by immature dendritic cells, which might make a difference in ameliorating colitis.…”

The Methyl-CpG-Binding Protein Mbd2 Regulates Susceptibility to Experimental Colitis via Control of CD11c+ Cells and Colonic Epithelium

“…Murine cDC1s (identified as CD11b − CD103 + XCR1 + ), equivalent to CD103 + Sirpα − DCs in humans, are dependent on transcription factors (TFs) Id2, Irf8, and Batf3 and induce anti-viral/bacterial IFNγ (Th1) CD4 + T cell responses (10). In contrast, CD11b + CD103 + intestinal cDC2s are related to CD103 + Sirpα + DCs in human intestines, depend on TFs Irf4 and Notch2 (10) and are important for induction of IL-17 (Th17) and IL-4/IL-5/IL-13 (Th2) CD4 + T cell responses (11). Whether epigenetic gene regulation is important in controlling immune responses of these subsets in the gut is unknown.…”