Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and β-cell protection

Dan Ploug Christensen, Conny Gysemans, Morten Lundh, Mattias Salling Dahllöf, Daniel Noesgaard, Søren Fisker Schmidt, Susanne Mandrup, Nikolai Birkbak, Christopher T. Workman, Lorenzo Piemonti, Lykke Blaabjerg, Valmen Monzani, Gianluca Fossati, Paolo Mascagni, Steven Paraskevas, Reid A. Aikin, Nils Billestrup, Lars Groth Grunnet, Charles A. Dinarello, Chantal Mathieu & 1 others Thomas Mandrup-Poulsen

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1055-1059
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number3
DOIs
Publication statusPublished - Jan 21 2014

Fingerprint

Cytoprotection
Inbred NOD Mouse
Lysine
Chromatin
Type 1 Diabetes Mellitus
Transcription Factors
Sirtuin 1
Insulin
Cytokines
Immunologic Factors
Peritoneal Macrophages
T-Lymphocyte Subsets
Regulatory T-Lymphocytes
Interleukin-12
Weaning
Interleukin-1
Drinking Water
Dendritic Cells
Autoimmune Diseases
Interleukin-6

Keywords

  • Autoimmunity
  • Epigenetics
  • Histone deacetylase
  • Inflammation
  • Posttranslational modification

ASJC Scopus subject areas

  • General

Cite this

Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and β-cell protection. / 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.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 3, 21.01.2014, p. 1055-1059.

Research output: Contribution to journalArticle

Christensen, DP, Gysemans, C, Lundh, M, Dahllöf, MS, Noesgaard, D, Schmidt, SF, Mandrup, S, Birkbak, N, Workman, CT, Piemonti, L, Blaabjerg, L, Monzani, V, Fossati, G, Mascagni, P, Paraskevas, S, Aikin, RA, Billestrup, N, Grunnet, LG, Dinarello, CA, Mathieu, C & Mandrup-Poulsen, T 2014, 'Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and β-cell protection', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 3, pp. 1055-1059. https://doi.org/10.1073/pnas.1320850111/-/DCSupplemental
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. / Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and β-cell protection. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 3. pp. 1055-1059.
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