Molecular Medicine

, Volume 17, Issue 5–6, pp 369–377 | Cite as

The Oral Histone Deacetylase Inhibitor ITF2357 Reduces Cytokines and Protects Islet β Cells In Vivo and In Vitro

  • Eli C Lewis
  • Lykke Blaabjerg
  • Joachim Størling
  • Sif G Ronn
  • Paolo Mascagni
  • Charles A Dinarello
  • Thomas Mandrup-Poulsen
Research Article


In type 1 diabetes, inflammatory and immunocompetent cells enter the islet and produce proinflammatory cytokines such as interleukin-1 β (IL-1β), IL-12, tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ); each contribute to β-cell destruction, mediated in part by nitric oxide. Inhibitors of histone deacetylases (HDAC) are used commonly in humans but also possess antiinflammatory and cytokine-suppressing properties. Here we show that oral administration of the HDAC inhibitor ITF2357 to mice normalized strep-tozotocin (STZ)-induced hyperglycemia at the clinically relevant doses of 1.25–2.5 mg/kg. Serum nitrite levels returned to nondiabetic values, islet function improved and glucose clearance increased from 14% (STZ) to 50% (STZ + ITF2357). In vitro, at 25 and 250 nmol/L, ITF2357 increased islet cell viability, enhanced insulin secretion, inhibited MIP-1 α and MIP-2 release, reduced nitric oxide production and decreased apoptosis rates from 14.3% (vehicle) to 2.6% (ITF2357). Inducible nitric oxide synthase (iNOS) levels decreased in association with reduced islet-derived nitrite levels. In peritoneal macrophages and splenocytes, ITF2357 inhibited the production of nitrite, as well as that of TNFα and IFNγ at an IC50 of 25–50 nmol/L. In the insulin-producing INS cells challenged with the combination of IL-1 β plus IFNγ, apoptosis was reduced by 50% (P < 0.01). Thus at clinically relevant doses, the orally active HDAC inhibitor ITF2357 favors β-cell survival during inflammatory conditions.



These studies were supported by NIH grants AI-15614, CA-04 6934 and Juvenile Diabetes Research Foundation grant 26-2008-893 (to CA Dinarello), Juvenile Diabetes Research Foundation grants 2-2007-103 (to EC Lewis), and 4-202-457 (to SG Ronn), the Danish Research Council (to J Størling) and Novo Nordisk (to L Blaabjerg and T Mandrup-Poulsen). We thank Anne-Sofie Hillesoe, Owen Bowers and Tania Azam for their excellent technical assistance.


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Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Eli C Lewis
    • 1
    • 2
  • Lykke Blaabjerg
    • 3
  • Joachim Størling
    • 3
  • Sif G Ronn
    • 3
  • Paolo Mascagni
    • 4
  • Charles A Dinarello
    • 1
  • Thomas Mandrup-Poulsen
    • 3
    • 5
    • 6
  1. 1.Department of MedicineUniversity of Colorado DenverAuroraUSA
  2. 2.Department of BiochemistryBen-Gurion University of the NegevBeer ShevaIsrael
  3. 3.Steno Diabetes Center and Hagedorn Research InstituteGentofteDenmark
  4. 4.Italfarmaco, SpACinisello BalsamoItaly
  5. 5.Department of Biomedical SciencesUniversity of CopenhagenCopenhagenDenmark
  6. 6.Center for Medical Research Methodology, Department of Biomedical Sciences, Institute of Biomedical Sciences the Panum InstituteUniversity of CopenhagenCopenhagen NDenmark

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