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

In type 1 diabetes, inflammatory and immunocompetent cells enter the islet and produce proinflammatory cytokines such as interleukin-1 beta (IL-1 beta), IL-12, tumor necrosis factor-alpha (INF alpha) and interferon-gamma (IFN gamma); each contribute to beta-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 streotozotocin (STZ)-induced hyperglycemia at the clinically relevant doses of 1.25-2.5 mg/kg. Serum nitrite levels returned to nondibetic 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 alpha 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 TNF alpha and IFN gamma at an IC50 of 25-50 nmol/L. In the insulin-producing INS cells challenged with the combination of IL-1 beta plus IFN gamma, apoptosis was reduced by 50% (P < 0.01). Thus at clinically relevant doses, the orally active HDAC inhibitor ITF2357 favors beta-cell survival during inflammatory conditions. (C) 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: http://www.molmed.org doi: 10.2119/molmed.2010.00152