title: 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.
authors.affiliation: Tytgat Institute for Gastro-Intestinal and Liver Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Schilderink
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area, Medicines Research Centre, GlaxoSmithKline, Stevenage United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bell
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area, Medicines Research Centre, GlaxoSmithKline, Stevenage United Kingdom.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Reginato
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area, Medicines Research Centre, GlaxoSmithKline, Stevenage United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Patten
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area, Medicines Research Centre, GlaxoSmithKline, Stevenage United Kingdom.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Rioja
authors.affiliation: Tytgat Institute for Gastro-Intestinal and Liver Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Francisca W
authors.initials: FW
authors.lastname: Hilbers
authors.affiliation: Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Pawel A
authors.initials: PA
authors.lastname: Kabala
authors.affiliation: Department of Experimental Immunology and Department of Clinical Immunology and Rheumatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Kris A
authors.initials: KA
authors.lastname: Reedquist
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area, Medicines Research Centre, GlaxoSmithKline, Stevenage United Kingdom.
authors.forename: David F
authors.initials: DF
authors.lastname: Tough
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area, Medicines Research Centre, GlaxoSmithKline, Stevenage United Kingdom.
authors.forename: Paul Peter
authors.initials: PP
authors.lastname: Tak
authors.affiliation: Epinova DPU, Immuno-Inflammation Therapy Area, Medicines Research Centre, GlaxoSmithKline, Stevenage United Kingdom.
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
authors.affiliation: Tytgat Institute for Gastro-Intestinal and Liver Research, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: w.j.dejonge@amc.nl.
authors.forename: Wouter J
authors.initials: WJ
authors.lastname: de Jonge
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018920:Coculture Techniques; D003092:Colitis / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: D016207:Cytokines; C568713:GSK1210151A; D006576:Heterocyclic Compounds, 4 or More Rings
keywords: Bromodomain; Dendritic cells; Epigenetics; Immune suppression; Tolerance