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Molecular Medicine

, Volume 11, Issue 1–12, pp 1–15 | Cite as

The Histone Deacetylase Inhibitor ITF2357 Reduces Production of Pro-Inflammatory Cytokines In Vitro and Systemic Inflammation In Vivo

  • Flavio Leoni
  • Gianluca Fossati
  • Eli C Lewis
  • Jae-Kwon Lee
  • Giulia Porro
  • Paolo Pagani
  • Daniela Modena
  • Maria Lusia Moras
  • Pietro Pozzi
  • Leonid L Reznikov
  • Britta Siegmund
  • Giamila Fantuzzi
  • Charles A Dinarello
  • Paolo Mascagni
Articles

Abstract

We studied inhibition of histone deacetylases (HDACs), which results in the unraveling of chromatin, facilitating increased gene expression. ITF2357, an orally active, synthetic inhibitor of HDACs, was evaluated as an anti-inflammatory agent. In lipopolysaccharide (LPS)-stimulated cultured human peripheral blood mononuclear cells (PBMCs), ITF2357 reduced by 50% the release of tumor necrosis factor-α (TNFα) at 10 to 22 nM, the release of intracellular interleukin (IL-1α at 12 nM, the secretion of IL-1β at 12.5 to 25 nM, and the production of interferon-γ (IFNγ) at 25 nM. There was no reduction in IL-8 in these same cultures. Using the combination of IL-12 plus IL-18, IFNγ and IL-6 production was reduced by 50% at 12.5 to 25 nM, independent of decreased IL-1 or TNFα. There was no evidence of cell death in LPS-stimulated PBMCs at 100 nM ITF2357, using assays for DNA degradation, annexin V, and caspase-3/7. By Northern blotting of PBMCs, there was a 50% to 90% reduction in LPS-induced steady-state levels of TNFα and IFNγ mRNA but no effect on IL-1β or IL-8 levels. Real-time PCR confirmed the reduction in TNFα RNA by ITF2357. Oral administration of 1.0 to 10 mg/kg ITF2357 to mice reduced LPS-induced serum TNFα and IFNγ by more than 50%. Anti-CD3-induced cytokines were not suppressed by ITF2357 in PBMCs either in vitro or in the circulation in mice. In concanavalin-A-induced hepatitis, 1 or 5 mg/kg of oral ITF2357 significantly reduced liver damage. Thus, low, nonapoptotic concentrations of the HDAC inhibitor ITF2357 reduce pro-inflammatory cytokine production in primary cells in vitro and exhibit anti-inflammatory effects in vivo.

Notes

Acknowledgements

These studies were supported by National Institutes of Health Grants Al-15614, HL-68743, and CA-04 6934 (all C.A.D.). B.S. was supported by the Deutsche Forschungsgemeinschaft 749/3–3. The authors thank Soo-Hyun Kim, Tania Azam, and Joseph Senello for assistance and Peter Loidl (University of Innsbruck, Department of Microbiology) for the maize HDAC enzyme assays.

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Copyright information

© Feinstein Institute for Medical Research 2005

Authors and Affiliations

  • Flavio Leoni
    • 1
  • Gianluca Fossati
    • 1
  • Eli C Lewis
    • 2
  • Jae-Kwon Lee
    • 2
  • Giulia Porro
    • 1
  • Paolo Pagani
    • 1
  • Daniela Modena
    • 1
  • Maria Lusia Moras
    • 1
  • Pietro Pozzi
    • 1
  • Leonid L Reznikov
    • 2
  • Britta Siegmund
    • 2
  • Giamila Fantuzzi
    • 2
  • Charles A Dinarello
    • 2
  • Paolo Mascagni
    • 1
  1. 1.Research CenterItalfarmaco, S. p. A.MilanItaly
  2. 2.University of Colorado Health Sciences CenterDenverUSA

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