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Selective inhibition of CD4⁺ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors
Hozefa S. Bandukwala, John Gagnon, Susan Togher, Jason A. Greenbaum, Edward D. Lamperti, Nigel J. Parr, Amy M. H. Molesworth, Nicholas Smithers, Kevin Lee, Jason Witherington, David F. Tough, Rab K. Prinjha, Bjoern Peters and Anjana Rao
Proceedings of the National Academy of Sciences of the United States of America
Vol. 109, No. 36 (September 4, 2012), pp. 14532-14537
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/41706242
Page Count: 6
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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 proteins of the bromodomain and extra-terminal domain (BET) family, was previously shown to suppress the production of proinf lammatory proteins by macrophages and block acute inflammation in mice. Here, we investigated the effect of short-term treatment with I-BET-762 on T-cell function. Treatment of naïve CD4⁺ T cells with I-BET-762 during the first 2 d of differentiation had long-lasting effects on subsequent gene expression and cytokine production. Gene expression analysis revealed up-regulated expression of several antiinflammatory gene products, including IL-10, Lag3, and Egr2, and down-regulated expression of several proinf lammatory cytokines including GM-CSF and IL-17. The short 2-d treatment with I-BET-762 inhibited the ability of antigen-specific T cells, differentiated under Th1 but not Th17 conditions in vitro, to induce pathogenesis in an adoptive transfer model of experimental autoimmune encephalomyelitis. The suppressive effects of I-BET-762 on T-cell mediated inflammation in vivo were accompanied by decreased recruitment of macrophages, consistent with decreased GM-CSF production by CNS-inf iltrating T cells. These effects were mimicked by an inhibitor of c-myc function, implicating reduced expression of c-myc and GM-CSF as one avenue by which I-BET-762 suppresses the inflammatory functions of T cells. Our study demonstrates that inhibiting the functions of BET-family proteins during early T-cell differentiation causes long-lasting suppression of the proinf lammatory functions of Th1 cells.
Proceedings of the National Academy of Sciences of the United States of America © 2012 National Academy of Sciences