Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 9, Pages 6142-6151Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.517599
Keywords
Colitis; Histone Deacetylase Inhibitors; Inflammatory Bowel Disease; Macrophages; STAT3; IL-6R; Il-17; T Helper Cells; Promoter Acetylation
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Funding
- Deutsche Forschungsgemeinschaft [SI 749/5-3]
- Helmholtz Alliance Preclinical Cancer Comprehensive Center
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Background: HDAC inhibitors exert anti-inflammatory properties. Results: ITF2357 shifts the balance from Th17 cells toward regulatory T cells via suppression of the IL-6R expression on naive T cells. Conclusion: The HDAC inhibitor ITF2357 modulates T cell polarization in experimental colitis. Significance: Learning the mode of action of this compound class will serve to optimize future therapeutic strategies. Histone deacetylase (HDAC) inhibitors have been associated primarily 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. Because 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 observed anti-inflammatory effects. Although HDAC inhibition suppressed the polarization toward 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 interleukin 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 STAT3 phosphorylation as well as retinoic acid receptor-related orphan receptor T (RORT) 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 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 the amelioration of disease. This 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.
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