Histone hyperacetylation is associated with amelioration of experimental colitis in mice.

Details

Serval ID
serval:BIB_708EF2286953
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Histone hyperacetylation is associated with amelioration of experimental colitis in mice.
Journal
Journal of Immunology
Author(s)
Glauben R., Batra A., Fedke I., Zeitz M., Lehr H.A., Leoni F., Mascagni P., Fantuzzi G., Dinarello C.A., Siegmund B.
ISSN
0022-1767
Publication state
Published
Issued date
2006
Peer-reviewed
Oui
Volume
176
Number
8
Pages
5015-5022
Abstract
Inhibitors of histone deacetylases (HDAC) are being studied for their antiproliferative effects in preclinical cancer trials. Recent studies suggest an anti-inflammatory role for this class of compounds. Because inflammatory bowel disease is associated with an increased risk of malignancies, agents with antiproliferative and anti-inflammatory properties would be of therapeutic interest. HDAC inhibitors from various classes were selected and evaluated for their in vitro capacity to suppress cytokine production and to induce apoptosis and histone acetylation. Valproic acid (VPA) and suberyolanilide hydroxamic acid (SAHA) were chosen for further studies in dextran sulfate sodium- and trinitrobenzene sulfonic acid-induced colitis in mice. In vitro, inhibition of HDAC resulted in a dose-dependent suppression of cytokine synthesis and apoptosis induction requiring higher concentrations of HDAC inhibitors for apoptosis induction compared with cytokine inhibition. Oral administration of either VPA or SAHA reduced disease severity in dextran sulfate sodium-induced colitis. The macroscopic and histologic reduction of disease severity was associated with a marked suppression of colonic proinflammatory cytokines. In parallel to the beneficial effect observed, a dose-dependent increase in histone 3 acetylation at the site of inflammation was shown under VPA treatment. Furthermore, SAHA as well as VPA treatment resulted in amelioration of trinitrobenzene sulfonic acid-induced colitis, which was associated with an increase of apoptosis of lamina propria lymphocytes. Inhibitors of HDAC reveal strong protective effects in different models of experimental colitis by inducing apoptosis and suppressing proinflammatory cytokines, thereby representing a promising class of compounds for clinical studies in human inflammatory bowel disease.
Keywords
Acetylation, Animals, Anti-Inflammatory Agents, Non-Steroidal, Apoptosis, Colitis, Cytokines, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Inhibitors, Female, Histone Deacetylases, Histones, Humans, Hydroxamic Acids, Mice, Mice, Inbred C57BL, Valproic Acid
Pubmed
Web of science
Create date
29/01/2008 18:33
Last modification date
20/08/2019 14:29
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