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 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.
- 23.Matalon S, et al. (2010) The histone deacetylase inhibitor ITF2357 decreases surface CXCR4 and CCR5 expression on CD4+ T-cells and monocytes and is superior to valproic acid for latent HIV-1 expression in vitro. J.Acquit. Immune Defic. Syndr. 54:1–9.Google Scholar
- 26.Donath M, et al. (2008) Xoma 052, an anti-IL-1beta antibody, in a double-blind, placebo controlled, dose escalation study of the safety and pharmacokinetocs in patients with type 2 diabetes mellitus, a new approach to therapy. Diabetologia. 51 Suppl 1:433.Google Scholar
- 31.Netea MG, etal. (2006) Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance. Nat. Med. 28:28.Google Scholar
- 47.Maedler K, et al. (2004) Glucose- and interleukin-1beta-induced beta-cell apoptosis requires Ca2+ influx and extracellular signal-regulated kinase (ERK) 1/2 activation and is prevented by a sul-fonylurea receptor 1/inwardly rectifying K+ channel 6.2 (SUR/Kir6.2) selective potassium channel opener in human islets. Diabetes. 53:1706–13.CrossRefPubMedGoogle Scholar