gsk1210151a and Colitis

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

Topics: Animals; Blotting, Western; Coculture Techniques; Colitis; Cytokines; Dendritic Cells; Disease Models, Animal; Flow Cytometry; Heterocyclic Compounds, 4 or More Rings; Humans; Immune Tolerance; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Polymerase Chain Reaction; T-Lymphocytes, Regulatory