title: Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and β-cell protection.
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.
authors.affiliation: Section for Endocrinological Research, Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Dan Ploug
authors.initials: DP
authors.lastname: Christensen
authors.forename: Conny
authors.initials: C
authors.lastname: Gysemans
authors.forename: Morten
authors.initials: M
authors.lastname: Lundh
authors.forename: Mattias Salling
authors.initials: MS
authors.lastname: Dahllöf
authors.forename: Daniel
authors.initials: D
authors.lastname: Noesgaard
authors.forename: Søren Fisker
authors.initials: SF
authors.lastname: Schmidt
authors.forename: Susanne
authors.initials: S
authors.lastname: Mandrup
authors.forename: Nikolai
authors.initials: N
authors.lastname: Birkbak
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Workman
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piemonti
authors.forename: Lykke
authors.initials: L
authors.lastname: Blaabjerg
authors.forename: Valmen
authors.initials: V
authors.lastname: Monzani
authors.forename: Gianluca
authors.initials: G
authors.lastname: Fossati
authors.forename: Paolo
authors.initials: P
authors.lastname: Mascagni
authors.forename: Steven
authors.initials: S
authors.lastname: Paraskevas
authors.forename: Reid A
authors.initials: RA
authors.lastname: Aikin
authors.forename: Nils
authors.initials: N
authors.lastname: Billestrup
authors.forename: Lars Groth
authors.initials: LG
authors.lastname: Grunnet
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
authors.forename: Thomas
authors.initials: T
authors.lastname: Mandrup-Poulsen
mesh_terms: D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D050990:GATA3 Transcription Factor / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007249:Inflammation; D050417:Insulin-Secreting Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D051381:Rats; D013997:Time Factors; D000077337:Vorinostat
chemical_list: D002843:Chromatin; D016207:Cytokines; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D006655:Histone Deacetylases
keywords: autoimmunity; epigenetics; histone deacetylase; inflammation; posttranslational modification