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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Lundh, Morten Billestrup, Nils Schmidt, Søren Fisker Aikin, Reid A. Birkbak, Nikolai Mandrup, Susanne Gysemans, Conny Workman, Christopher T. Grunnet, Lars Groth Dinarello, Charles A. Blaabjerg, Lykke Piemonti, Lorenzo Dahllöf, Mattias Salling Mandrup-poulsen, Thomas Mascagni, Paolo Paraskevas, Steven Mathieu, Chantal Monzani, Valmen Fossati, Gianluca Noesgaard, Daniel Christensen, Dan Ploug |
| Description | Author Affiliation: Christensen DP ( Section for Endocrinological Research, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.); |
| Abstract | Type 1 diabetes is due to destruction of pancreatic ß-cells. Lysine deacetylase inhibitors (KDACi) protect ß-cells from inflammatory destruction in vitro and are promising immunomodulators. Here we demonstrate that the clinically well-tolerated KDACi vorinostat and givinostat revert diabetes in the nonobese diabetic (NOD) mouse model of type 1 diabetes and counteract inflammatory target cell damage by a mechanism of action consistent with transcription factor--rather than global chromatin--hyperacetylation. Weaning NOD mice received low doses of vorinostat and givinostat in their drinking water until 100-120 d of age. Diabetes incidence was reduced by 38% and 45%, respectively, there was a 15% increase in the percentage of islets without infiltration, and pancreatic insulin content increased by 200%. Vorinostat treatment increased the frequency of functional regulatory T-cell subsets and their transcription factors Gata3 and FoxP3 in parallel to a decrease in inflammatory dendritic cell subsets and their cytokines IL-6, IL-12, and TNF- . KDACi also inhibited LPS-induced Cox-2 expression in peritoneal macrophages from C57BL/6 and NOD mice. In insulin-producing ß-cells, givinostat did not upregulate expression of the anti-inflammatory genes Socs1-3 or sirtuin-1 but reduced levels of IL-1ß + IFN-γ-induced proinflammatory Il1a, Il1b, Tnf , Fas, Cxcl2, and reduced cytokine-induced ERK phosphorylation. Further, NF-κB genomic iNos promoter binding was reduced by 50%, and NF-κB-dependent mRNA expression was blocked. These effects were associated with NF-κB subunit p65 hyperacetylation. Taken together, these data provide a rationale for clinical trials of safety and efficacy of KDACi in patients with autoimmune disease such as type 1 diabetes. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 3 |
| Volume Number | 111 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2014-01-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Chromatin Metabolism Diabetes Mellitus, Type 1 Histone Deacetylase Inhibitors Pharmacology Insulin-Secreting Cells Cytology Animals Cell Line Cytokines Disease Models, Animal Epigenesis, Genetic GATA3 Transcription Factor Histone Deacetylases Hydroxamic Acids Inflammation Mice Mice, Inbred C57BL Mice, Inbred NOD Phosphorylation Promoter Regions, Genetic Protein Binding Protein Processing, Post-Translational Time Factors Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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