Abstract
Post-translational modifications of histones, particularly acetylation, are associated with the regulation of inflammatory gene expression. We used two animal models of inflammation of the bowel and biopsy samples from patients with Crohn's disease (CD) to study the expression of acetylated histones (H) 3 and 4 in inflamed mucosa. Acetylation of histone H4 was significantly elevated in the inflamed mucosa in the trinitrobenzene sulfonic acid model of colitis particularly on lysine residues (K) 8 and 12 in contrast to non-inflamed tissue. In addition, acetylated H4 was localised to inflamed tissue and to Peyer's patches (PP) in dextran sulfate sodium (DSS)-treated rat models. Within the PP, H3 acetylation was detected in the mantle zone whereas H4 acetylation was seen in both the periphery and the germinal centre. Finally, acetylation of H4 was significantly upregulated in inflamed biopsies and PP from patients with CD. Enhanced acetylation of H4K5 and K16 was seen in the PP. These results demonstrate that histone acetylation is associated with inflammation and may provide a novel therapeutic target for mucosal inflammation.
Highlights
The cause of inflammatory bowel disease (IBD) remains unknown
Histone acetylation in inflamed and non-inflamed regions of the colon in the rat trinitrobenzene sulfonic acid (TNBS) model of colitis TNBS induced a significant increase in pan histone 4 acetylation in the distal (592 ± 54% vs 135 ± 24 Sham operated animals, p < 0.05) and the proximal regions of the colon (315 ± 39% vs 125 ± 19% sham operated animals, p < 0.05) with the inflamed distal region showing a greater increase (Figure 1B)
There was no significant induction of K5 or K16 induction by TNBS in the inflamed distal region (Figure 2)
Summary
The cause of inflammatory bowel disease (IBD) remains unknown. The main forms of IBD are Crohn’s disease and Ulcerative colitis. The effect of the HDAC inhibitors could be due to the large number of non-histone targets [18] including transcription factors such as NF-B, cytoskeletal proteins and cell cycle regulators thereby affecting inflammatory gene expression but cell proliferation and survival [19,20]. Experimental Procedures Animal tissue samples Two models of experimental colitis were chosen in order to depict different pathologic features associated with Crohn’s disease and Ulcerative colitis and to possibly compare different patterns of histone acetylation with different pathologic features. Immunohistochemistry The slides were fixed for 10 min in chilled acetone and allowed to air dry for a further 10 mins They were incubated for 1 hr in Quench Endogenous Peroxidase (3% H2O2 in PBS containing 0.02% Sodium Azide). We performed all statistical testing by using a two-sided 5% level of significance
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