The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet β cells in vivo and in vitro.

Abstract

In type 1 diabetes, inflammatory and immunocompetent cells enter the islet and produce proinflammatory cytokines such as interleukin-1β (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 streptozotocin (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-1α 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 IC(50) of 25-50 nmol/L. In the insulin-producing INS cells challenged with the combination of IL-1β 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.

• Authors: Eli C Lewis, Lykke Blaabjerg, Joachim Størling, Sif G Ronn, Paolo Mascagni, Charles A Dinarello, Thomas Mandrup-Poulsen
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) 2011 May-Jun Vol. 17 Issue 5-6 Pg. 369-77 ISSN: 1528-3658 [Electronic] England
• PMID: 21193899 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Hydroxamic Acids
• Interleukin-1beta
• Nitrites
• Nitric Oxide
• Streptozocin
• Interferon-gamma
• Nitric Oxide Synthase Type II
• givinostat hydrochloride

Topics

• Animals
• Cell Line
• Cells, Cultured
• Cytokines (metabolism)
• Female
• Glucose Tolerance Test
• Hydroxamic Acids (pharmacology, therapeutic use)
• Hyperglycemia (blood, chemically induced, prevention & control)
• Immunoblotting
• In Situ Nick-End Labeling
• In Vitro Techniques
• Insulin-Secreting Cells (drug effects)
• Interferon-gamma (pharmacology)
• Interleukin-1beta (pharmacology)
• Islets of Langerhans (drug effects, metabolism)
• Macrophages, Peritoneal (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (metabolism)
• Nitrites (blood)
• Rats
• Spleen (cytology)
• Streptozocin (toxicity)