HDACs and Inflammatory Bowel Disease

Inflammatory bowel disease is characterized by an overwhelming immune response causing an imbalance of the gut homeostasis. The etiology is still unknown and current therapies go along with severe side effects. While our group has already shown that pan-HDAC inhibitors ameliorate experimental colitis, we here further characterize this effect on a cellular level and analyze the role of specific HDAC in the inflammatory process. In the presence of the HDAC inhibitor ITF2357, the generation of FoxP3+ cells from naïve T helper cells was enhanced, the polarization to the pro-inflammatory Th17 cells suppressed, which was paralleled by a profound down regulation of the IL6 receptor. In macrophages, ITF2357 treatment leads to a dose-dependent down regulation of pro-inflammatory cytokines. In vitro experiments revealed HDAC5 dependent changes in the inflammatory profile of T cells and macrophages and PCR analysis disclosed HDAC5 as differentially expressed in polarized T helper cells. Further experimental colitis models demonstrate a more severe disease pattern for HDAC5 knockout mice compared to wild type mice. This was shown by an increased histological disease score, higher weight loss and severe intestinal bleeding. Isolation and analysis of lamina propria mononuclear cells confirmed these results by demonstrating alterations in the T cell composition.This study demonstrates, that inhibition of HDAC results in an anti-inflammatory phenotype in both, cells from the adaptive as well as the innate immune system. Furthermore, our data suggest a critical role of HDAC5 in the pro-inflammatory immune response in general and in particular in the pathogenesis of Colitis.