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

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

In type 1 diabetes, inflammatory and immunocompetent cells enter the islet and produce proinflammatory cytokines such as interleukin-1ß (IL-1ß), IL-12, tumor necrosis factor-a (TNFa) and interferon-¿ (IFN¿); each contribute to ß-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-1a 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 TNFa and IFN¿ at an IC(50) of 25-50 nmol/L. In the insulin-producing INS cells challenged with the combination of IL-1ß plus IFN¿, apoptosis was reduced by 50% (P <0.01). Thus at clinically relevant doses, the orally active HDAC inhibitor ITF2357 favors ß-cell survival during inflammatory conditions.
OriginalsprogEngelsk
TidsskriftMolecular Medicine
Vol/bind17
Udgave nummer5-6
Sider (fra-til)369-377
Antal sider9
ISSN0918-6557
DOI
StatusUdgivet - maj 2011

ID: 33901375