title: 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.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Eli C
authors.initials: EC
authors.lastname: Lewis
authors.forename: Lykke
authors.initials: L
authors.lastname: Blaabjerg
authors.forename: Joachim
authors.initials: J
authors.lastname: Størling
authors.forename: Sif G
authors.initials: SG
authors.lastname: Ronn
authors.forename: Paolo
authors.initials: P
authors.lastname: Mascagni
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Thomas
authors.initials: T
authors.lastname: Mandrup-Poulsen
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005951:Glucose Tolerance Test; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use*; D006943:Hyperglycemia / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D051381:Rats; D013154:Spleen / Q000166:cytology; D013311:Streptozocin / Q000633:toxicity
chemical_list: D016207:Cytokines; D006877:Hydroxamic Acids; D053583:Interleukin-1beta; D009573:Nitrites; D009569:Nitric Oxide; D013311:Streptozocin; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C502418:givinostat hydrochloride