Title: Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and β-cell protection
Authors: Christensen, Dan Ploug *
Gysemans, Conny *
Lundh, Morten
Dahllöf, Mattias Salling
Noesgaard, Daniel
Schmidt, Søren Fisker
Mandrup, Susanne
Birkbak, Nikolai
Workman, Christopher T
Piemonti, Lorenzo
Blaabjerg, Lykke
Monzani, Valmen
Fossati, Gianluca
Mascagni, Paolo
Paraskevas, Steven
Aikin, Reid A
Billestrup, Nils
Grunnet, Lars Groth
Dinarello, Charles A
Mathieu, Chantal
Mandrup-Poulsen, Thomas # ×
Issue Date: Jan-2014
Publisher: National Academy of Sciences
Series Title: Proceedings of the National Academy of Sciences of the United States of America vol:111 issue:3 pages:1055-9
Article number: 10.1073/pnas.1320850111
Abstract: Type 1 diabetes is due to destruction of pancreatic β-cells. Lysine deacetylase inhibitors (KDACi) protect β-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-α. KDACi also inhibited LPS-induced Cox-2 expression in peritoneal macrophages from C57BL/6 and NOD mice. In insulin-producing β-cells, givinostat did not upregulate expression of the anti-inflammatory genes Socs1-3 or sirtuin-1 but reduced levels of IL-1β + IFN-γ-induced proinflammatory Il1a, Il1b, Tnfα, 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: 0027-8424
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical and Experimental Endocrinology
* (joint) first author
× corresponding author
# (joint) last author

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