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.inflammation | histone deacetylase | posttranslational modification | epigenetics | autoimmunity

Specific Inhibition of Histone Deacetylase 8 Reduces Gene Expression and Production of Proinflammatory Cytokines in Vitro and in Vivo

“…In vitro, ITF2357 at 62.5 and 125 nM reduced cytokine-induced toxicity in rat and mouse beta cells (17,41). In the non-obese diabetic mouse model of Type 1 diabetes, ITF2357 added to the drinking water prevented the spontaneous development of diabetes (6). The daily dose of ITF2357 in that study was calculated at 1 mg/kg.…”

“…Although HDACs deacetylate the highly conserved N-terminal lysines on nuclear histones, HDACs also target cytosolic proteins, such as transcription factors and proteins, that regulate cell proliferation, migration, and death (4). HDAC inhibitors hyperacetylate signal transducers and activators of transcription (STAT) (5) and NFB, both of which are associated with decreased inflammation (6).…”

The Role of Butyrate, A Histone Deacetylase Inhibitor in Diabetes Mellitus: Experimental Evidence for Therapeutic Intervention

“…Additionally, HDACi prevent the development of virus-induced T1DM by the modulation of immune response during diabetes progression [56]. However, it has also been reported that vorinostat, an HDACi, protects β-cells and prevents diabetes progression by chromatin-independent mechanism [57].…”

Are epigenetic drugs for diabetes and obesity at our door step?

“…Recent studies have yielded evidence that suggests a significant role for vorinostat in the treatment or prevention of both T1DM and T2DM because of its HDACi effects. It has been associated with b cell protection when given as monotherapy and as adjunctive therapy [23,24], and reduction of renal complications in patients with DM.…”

“…Givinostat was shown to revert diabetes in the NOD mouse, and also to protect against the recurrence of autoimmune diabetes after treatment discontinuation. It was found to have proinflammatory cytokine-suppressing properties and to protect pancreatic b cells from inflammatory destruction and infiltration in vitro at nM concentrations [24]. Importantly, these effects were achieved with low doses of givinostat (nearly 100 times lower concentrations) than those needed to reduce tumor size in animals.…”