ACS DIVISION OF BIOLOGICAL CHEMISTRY

January 13th, 2014 by Glauben, R., Sonnenberg, E., Wetzel, M., Mascagni, P., Siegmund, B.

Histone deacetylase (HDAC) inhibitors have primarily been associated with an anti-proliferative effect in vitro and in vivo. Recent data provide evidence for an anti-inflammatory potency of HDAC inhibitors in models of experimental colitis. As the balance of T cell subpopulations is critical for the balance of the mucosal immune system, this study explores the regulatory potency of HDAC inhibitors on T cell polarization as a mechanistic explanation for the anti-inflammatory effects observed. While HDAC inhibition suppressed the polarization towards the pro-inflammatory T helper 17 (Th17) cells, it enhanced forkhead box P3 (FoxP3)+ regulatory T cell polarization in vitro and in vivo at the site of inflammation in the lamina propria. This was paralleled by a down-regulation of the IL-6 receptor (IL 6R) on naive CD4+ T cells on the mRNA as well as on the protein level, and changes in the chromatin acetylation at the IL6R gene and its promoter. Downstream of the IL-6R, HDAC inhibition was followed by a decrease in signal transducer and activation of transcription 3 (STAT3) phosphorylation as well as RAR-related orphan receptor T (RORγT) expression, thus identifying the IL 6/STAT3/IL-17 pathway as an important target of HDAC inhibitors. These results directly translated to experimental colitis, where the IL-6R expression was suppressed in naive T cells, paralleled by a significant reduction of Th17 cells in the lamina propria of ITF2357-treated animals resulting in amelioration of disease. The present study indicates that in experimental colitis inhibition of HDAC exerts an anti-inflammatory potency by directing T helper cell polarization via targeting the IL-6 pathway.