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Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors

ABSTRACT: Bromodomain-containing proteins bind acetylated lysine residues on histone tails and are involved in the recruitment of additional factors that mediate histone modifications and enable transcription. A compound, I-BET-762, that inhibits binding of an acetylated histone peptide to BRD4 and other proteins of the BET (bromodomain and extra-terminal domain) family, was previously shown to suppress the production of pro-inflammatory proteins by macrophages and block acute inflammation in mice. Here we investigate the effect of I-BET-762 on T cell function. We show that treatment of naïve CD4+ T cells with I-BET-762 during early differentiation modulates subsequent cytokine production, and inhibits the ability of Th1-skewed cells to induce autoimmune pathogenesis in a model of experimental autoimmune encephalomyelitis (EAE) in vivo. The suppressive effects of I-BET-762 on T-cell mediated inflammation were not due to inhibition of expression of the pro-inflammatory cytokines, IFN-. or IL-17, but correlated with the ability to suppress GM-CSF production from CNS-infiltrating T cells, resulting in decreased recruitment of macrophages and granulocytes. The effects of I-BET-762 were distinct from those of the fumarate ester, dimethyl fumarate (DMF), a candidate drug for treatment of multiple sclerosis (MS). Our data suggest that I-BET and DMF could have complementary roles in the treatment of MS, and provide a strong rationale for inhibitors of BET-family proteins in the treatment of autoimmune diseases, based on their dual ability to suppress granulocyte and macrophage recruitment by T cells as well as production of pro-inflammatory proteins by macrophages. RNA from resting or activated CD4+ T cells grown in the presence of a control substance (DMSO or Control-768) or two different concentrations of I-BET-762, was hybridized to the chip. There are 3 biological replicates for a total of 2 (cell states) x 4 (conditions) x 3 (replicates) = 24 samples.

ORGANISM(S): Mus musculus  

SUBMITTER: Jason Witherington   Kevin Lee  Jason Greenbaum  Hozefa S Bandukwala  Bjoern Peters  Nigel Parr  John Gagnon  Rab K Prinjha  Jason A Greenbaum  Nicholas Smithers  Anjana Rao  Eward D Lamperti  Amy M Molesworth  Susan Togher  David F Tough 

PROVIDER: E-GEOD-39886 | ArrayExpress | 2012-08-03



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