Abstract
This review, comprised of our own data and that of others, provides a summary overview of histone deacetylase (HDAC) inhibition on intestinal inflammation as well as inflammation-mediated carcinogenesis. Experimental colitis in mice represents an excellent in vivo model to define the specific cell populations and target tissues modulated by inhibitors of HDAC. Oral administration of either suberyolanilide hydroxamic acid (SAHA) or ITF2357 results in an amelioration in these models, as indicated by a significantly reduced colitis disease score and histological score. This effect was paralleled by suppression of proinflammatory cytokines at the site of inflammation as well as specific changes in the composition of cells within the lamina propria. In addition, tumor number and size was significantly reduced in two models of inflammation-driven tumorigenesis, namely interleukin (IL)-10-deficient mice and the azoxymethane-dextran sulfate sodium (DSS) model, respectively. The mechanisms affected by HDAC inhibition, contributing to this antiinflammatory and antiproliferative potency will be discussed in detail. Furthermore, with regard to the relevance in human inflammatory bowel disease, the doses of ITF2357 considered safe in humans and the corresponding serum concentrations are consistent with the efficacious dosing used in our in vivo as well as in vitro experiments. Thus, the data strongly suggest that HDAC inhibitors could serve as a therapeutic option in inflammatory bowel disease.
Highlights
Inflammatory bowel disease is a chronic disorder that accompanies patients throughout their lives
These experiments were not performed in immune cells, it is obvious that miRNA expression modulated by histone deacetylase (HDAC) inhibitors represents a promising new field to investigate the mode of action of these compounds, since today, miRNAs are emerging as key regulators of the immune response [54]
The HDAC inhibitors reach the site of inflammation and exert their therapeutic potency, whereas there are no side effects related to the gastrointestinal tract
Summary
Inflammatory bowel disease is a chronic disorder that accompanies patients throughout their lives. This transcriptional regulation by GATA-3/T-bet and HDAC3/HDAC5 interactions is a possible way to explain lineage-specific (Th1/Th2) protein expression, which is of particular interest in IBD, where the Th1/Th2 balance was taken for years as one feature of Crohn’s disease (Th1) or ulcerative colitis (Th2) This exact discrimination is not further supported according to the recent literature [31], the cytokine milieu at the site of inflammation represents a crucial characteristic, defining progress and severity of IBD, important both for diagnosis as well as for therapy. LAQ824 is followed by rapid and significant changes in 40% of the different miRNA species expressed in SKBr3, a cancer cell line, with 22 miRNA species downregulated and 5 miRNAs upregulated [53] These experiments were not performed in immune cells, it is obvious that miRNA expression modulated by HDAC inhibitors represents a promising new field to investigate the mode of action of these compounds, since today, miRNAs are emerging as key regulators of the immune response [54]. Inhibitors of HDAC induce Stat acetylation, and only acetylated Stat interacts with p65, resulting in a NF-κB inactivation by translocation of p65 to the cytoplasm [67]
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