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Molecular Medicine

, Volume 17, Issue 5–6, pp 369–377 | Cite as

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

  • Eli C Lewis
  • Lykke Blaabjerg
  • Joachim Størling
  • Sif G Ronn
  • Paolo Mascagni
  • Charles A Dinarello
  • Thomas Mandrup-Poulsen
Research Article

Abstract

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.

Notes

Acknowledgments

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.

References

  1. 1.
    Khan N, et al. (2008) Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. Biochem. J. 409:581–9.CrossRefPubMedGoogle Scholar
  2. 2.
    Gerstner T, Bell N, Konig S. (2008) Oral valproic acid for epilepsy—long-term experience in therapy and side effects. Expert Opin. Pharmacother. 9:285–92.CrossRefPubMedGoogle Scholar
  3. 3.
    Ren M, Leng Y, Jeong M, Leeds PR, Chuang DM. (2004) Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat shock protein induction. J. Neurochem. 89:1358–67.CrossRefPubMedGoogle Scholar
  4. 4.
    Archin NM, et al. (2008) Valproic acid without intensified antiviral therapy has limited impact on persistent HIV infection of resting CD4+ T cells. Aids. 22:1131–5.CrossRefPubMedGoogle Scholar
  5. 5.
    Atweh GF, Loukopoulos D. (2001) Pharmacological induction of fetal hemoglobin in sickle cell disease and beta-thalassemia. Semin. Hematol 38:367–73.CrossRefPubMedGoogle Scholar
  6. 6.
    Atweh GF, Schechter AN. (2001) Pharmacologic induction of fetal hemoglobin: raising the therapeutic bar in sickle cell disease. Curr. Opin. Hematol. 8:123–30.CrossRefPubMedGoogle Scholar
  7. 7.
    Marks PA, et al. (2001) Histone deacetylases and cancer: causes and therapies. Nature Rev. Cancer 1:194–202.CrossRefGoogle Scholar
  8. 8.
    O’Connor OA, et al. (2006) Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoy-lanilide hydroxamic acid in patients with advanced hematologic malignancies. J. Clin. Oncol. 24:166–73.CrossRefPubMedGoogle Scholar
  9. 9.
    Richon VM, Zhou X, Rifkind RA, Marks PA. (2001) Histone deacetylase inhibitors: development of suberoylanilide hydroxamic acid (SAHA) for the treatment of cancers. Blood Cells Mol. Dis. 27:260–4.CrossRefPubMedGoogle Scholar
  10. 10.
    Park JH, et al. (2004) Class I histone deacetylase-selective novel synthetic inhibitors potently inhibit human tumor proliferation. Clin. Cancer Res. 10:5271–81.CrossRefPubMedGoogle Scholar
  11. 11.
    Santini V, Gozzini A, Ferrari G. (2007) Histone deacetylase inhibitors: molecular and biological activity as a premise to clinical application. Curr. DrugMetab. 8:383–93.CrossRefGoogle Scholar
  12. 12.
    Garcia-Manero G, et al. (2008) Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood. 111:1060–6.CrossRefPubMedGoogle Scholar
  13. 13.
    Leoni F, et al. (2002) The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines. Proc. Natl. Acad. Sci. U. S. A. 99:2995–3000.CrossRefPubMedGoogle Scholar
  14. 14.
    Reddy P, et al. (2004) Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect. Proc. Natl. Acad. Sci. U. S. A. 101:3921–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Reilly CM, et al. (2004) Modulation of renal disease in MRL/lpr mice by suberoylanilide hydroxamic acid. J. Immunol. 173:4171–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Glauben R, et al. (2006) Histone hyperacetylation is associated with amelioration of experimental colitis in mice. J. Immunol. 176:5015–22.CrossRefPubMedGoogle Scholar
  17. 17.
    Leoni F, et al. (2005) The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol. Med. 11:1–15.CrossRefPubMedGoogle Scholar
  18. 18.
    Leng C, et al. (2006) Reduction of graft-versus-host disease by histone deacetylase inhibitor suberonylanilide hydroxamic acid is associated with modulation of inflammatory cytokine milieu and involves inhibition of STAT1. Exp. Hematol. 34:776–87.CrossRefPubMedGoogle Scholar
  19. 19.
    Shein NA, et al. (2009) Histone deacetylase inhibitor ITF2357 is neuroprotective, improves functional recovery, and induces glial apoptosis following experimental traumatic brain injury. FASEB J. 23:4266–75.CrossRefPubMedGoogle Scholar
  20. 20.
    Glauben R, et al. (2008) Histone deacetylases: novel targets for prevention of colitis-associated cancer in mice. Gut. 57:613–22.CrossRefPubMedGoogle Scholar
  21. 21.
    Carta S, et al. (2006) Histone deacetylase inhibitors prevent exocytosis of interleukin-1beta-containing secretory lysosomes: role of microtubules. Blood. 108:1618–26.CrossRefPubMedGoogle Scholar
  22. 22.
    Bosisio D, et al. (2008) Blocking TH17-polarizing cytokines by histone deacetylase inhibitors in vitro and in vivo. J. Leukoc. Biol. 84:1540–8.CrossRefPubMedGoogle Scholar
  23. 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
  24. 24.
    Guerini V, et al. (2008) The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F). Leukemia. 22:740–747.CrossRefPubMedGoogle Scholar
  25. 25.
    Vojinovic J, et al. (2011) Safety and efficacy of an oral histone deacetylase inhibitor in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 63:1452–8.CrossRefPubMedGoogle Scholar
  26. 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
  27. 27.
    Larsen CM, et al. (2007) Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356:1517–26.CrossRefPubMedGoogle Scholar
  28. 28.
    Larsen L, et al. (2007) Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells. Diabetologia. 50:779–89.CrossRefPubMedGoogle Scholar
  29. 29.
    Susick L, Veluthakal R, Suresh MV, Hadden T, Kowluru A. (2008) Regulatory roles for histone deacetylation in IL-1beta-induced nitric oxide release in pancreatic beta-cells. J. Cell Mol. Med. 12:1571–83.CrossRefPubMedGoogle Scholar
  30. 30.
    Lundh M, et al. (2010) Lysine deacetylases are produced in pancreatic beta cells and are differentially regulated by proinflammatory cytokines. Diabetologia. 53:2569–78.CrossRefPubMedGoogle Scholar
  31. 31.
    Netea MG, etal. (2006) Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance. Nat. Med. 28:28.Google Scholar
  32. 32.
    Lewis EC, Dinarello CA. (2006) Responses of IL-18-and IL-18 receptor-deficient pancreatic islets with convergence of positive and negative signals for the IL-18 receptor. Proc. Natl. Acad. Sci. U. S. A. 103:16852–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Fantuzzi G, et al. (2003) Generation and characterization of mice transgenic for human IL-18-binding protein isoform a. J. Leukoc. Biol. 74:889–96.CrossRefPubMedGoogle Scholar
  34. 34.
    Fantuzzi G, Reed D, Dinarello CA. (1999) IL-12-induced IFN-gamma is dependent on caspase-1 processing of the IL-18 precursor. J. Clin. Invest. 104:761–7.CrossRefPubMedGoogle Scholar
  35. 35.
    Larsen L, et al. (2005) Extracellular signal-regulated kinase is essential for interleukin-1-induced and nuclear factor kappaB-mediated gene expression in insulin-producing INS-1E cells. Diabetologia. 48:2582–90.CrossRefPubMedGoogle Scholar
  36. 36.
    Oldoni T, Furlan A, Monznani V, Dinarello CA. (2009) Decreased whole blood cytokine production during a phase I trial of the histone deacety-lase inhibitor ITF2357 [abstract]. Cytokine. 48:120.CrossRefGoogle Scholar
  37. 37.
    Sandberg JO, Andersson A, Eizirik DL, Sandler S. (1994) Interleukin-1 receptor antagonist prevents low dose streptozotocin induced diabetes in mice. Biochem. Biophys. Res. Commun. 202:543–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Bleich D, et al. (1995) Interleukin-1 beta regulates the expression of a leukocyte type of 12-lipoxy-genase in rat islets and RIN m5F cells. Endocrinology. 136:5736–44.CrossRefPubMedGoogle Scholar
  39. 39.
    Mandrup-Poulsen T, Pickersgill L, Donath MY. (2010) Blockade of interleukin 1 in type 1 diabetes mellitus. Nat. Rev. Endocrinol. 6:158–66.CrossRefPubMedGoogle Scholar
  40. 40.
    Marisa C, et al. (2005) MCP-1 and MIP-2 expression and production in BB diabetic rat: effect of chronic hypoxia. Mol. Cell Biochem. 276:105–11.CrossRefPubMedGoogle Scholar
  41. 41.
    Cameron MJ, et al. (2000) Differential expression of CC chemokines and the CCR5 receptor in the pancreas is associated with progression to type I diabetes. J. Immunol. 165:1102–10.CrossRefPubMedGoogle Scholar
  42. 42.
    Toubi E, Shoenfeld Y. (2004) The role of CD40-CD154 interactions in autoimmunity and the benefit of disrupting this pathway. Autoimmunity. 37:457–64.CrossRefPubMedGoogle Scholar
  43. 43.
    Skov S, et al. (2003) Histone deacetylase inhibitors: a new class of immunosuppressors targeting a novel signal pathway essential for CD154 expression. Blood. 101:1430–8.CrossRefPubMedGoogle Scholar
  44. 44.
    Reddy P, et al. (2008) Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice. J. Clin. Invest. 118:2562–73.PubMedCentralPubMedGoogle Scholar
  45. 45.
    Sun Y, et al. (2009) Cutting edge: Negative regulation of dendritic cells through acetylation of the nonhistone protein STAT-3. J. Immunol. 182:5899–903.CrossRefPubMedGoogle Scholar
  46. 46.
    Bode KA, et al. (2007) Histone deacetylase inhibitors decrease Toll-like receptor-mediated activation of proinflammatory gene expression by impairing transcription factor recruitment. Immunology. 122:596–606.CrossRefPubMedGoogle Scholar
  47. 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
  48. 48.
    Maedler K, et al. (2002) Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J. Clin. Invest. 110:851–60.CrossRefPubMedGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Eli C Lewis
    • 1
    • 2
  • Lykke Blaabjerg
    • 3
  • Joachim Størling
    • 3
  • Sif G Ronn
    • 3
  • Paolo Mascagni
    • 4
  • Charles A Dinarello
    • 1
  • Thomas Mandrup-Poulsen
    • 3
    • 5
    • 6
  1. 1.Department of MedicineUniversity of Colorado DenverAuroraUSA
  2. 2.Department of BiochemistryBen-Gurion University of the NegevBeer ShevaIsrael
  3. 3.Steno Diabetes Center and Hagedorn Research InstituteGentofteDenmark
  4. 4.Italfarmaco, SpACinisello BalsamoItaly
  5. 5.Department of Biomedical SciencesUniversity of CopenhagenCopenhagenDenmark
  6. 6.Center for Medical Research Methodology, Department of Biomedical Sciences, Institute of Biomedical Sciences the Panum InstituteUniversity of CopenhagenCopenhagen NDenmark

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