The oral histone deacetylase inhibitor ITF2357 reduces cytokine production, cytokine activities and protects islet β-cells in vivo and in vitro

Lewis, Eli C.; Blaabjerg, Lykke; Størling, Joachim; Rønn, Sif G.; Mascagni, Paolo; Dinarello, Charles A.; Mandrup‐Poulsen, Thomas

doi:10.1016/j.cyto.2009.07.387

Cited by 5 publications

(15 citation statements)

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“…Thus, HDACi, such as givinostat, vorinostat and trichostatin A, reduce cytokineinduced beta cell toxicity and restore insulin secretion in vitro and in vivo [12,14,15,22,24]. However, all HDACi in current clinical use are non-selective, and it is not known which of the 11 HDACs produced by the beta cell [12] mediate the toxic effects of cytokines.…”

Section: Discussionmentioning

confidence: 99%

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Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children

et al. 2012

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Aims/hypothesis Histone deacetylases (HDACs) are promising pharmacological targets in cancer and autoimmune diseases. All 11 classical HDACs (HDAC1-11) are found in the pancreatic beta cell, and HDAC inhibitors (HDACi) protect beta cells from inflammatory insults. We investigated which HDACs mediate inflammatory beta cell damage and how the islet content of these HDACs is regulated in recent-onset type 1 diabetes. Methods The rat beta cell line INS-1 and dispersed primary islets from rats, either wild type or HDAC1-3 deficient, were exposed to cytokines and HDACi. Molecular mechanisms were investigated using real-time PCR, chromatin immunoprecipitation and ELISA assays. Pancreases from healthy children and children with type 1 diabetes were assessed using immunohistochemistry and immunofluorescence. Results Screening of 19 compounds with different HDAC selectivity revealed that inhibitors of HDAC1, -2 and -3 rescued INS-1 cells from inflammatory damage. Small hairpin RNAs against HDAC1 and -3, but not HDAC2, reduced pro-inflammatory cytokine-induced beta cell apoptosis in INS-1 and primary rat islets. The protective properties of specific HDAC knock-down correlated with attenuated cytokine-induced iNos expression but not with altered expression of the proinflammatory mediators Il1α, Il1β, Tnfα or Cxcl2. HDAC3 knock-down reduced nuclear factor κB binding to the iNos promoter and HDAC1 knock-down restored insulin secretion. In pancreatic sections from children with type 1 diabetes of recent onset, HDAC1 was upregulated in beta cells whereas HDAC2 and -3 were downregulated in comparison with five paediatric controls. Conclusions/interpretation These data demonstrate nonredundant functions of islet class I HDACs and suggest that targeting HDAC1 and HDAC3 would provide optimal protection of beta cell mass and function in clinical islet transplantation and recent-onset type 1 diabetic patients.

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Section: Discussionmentioning

confidence: 99%

“…HDAC inhibition blocks cytokine-induced inducible nitric oxide synthase (iNOS) production [12,14,22]. We therefore investigated whether a deficiency in HDAC1, -2 or -3 affected cytokine-mediated iNos induction in INS-1 cells.…”

Section: Resultsmentioning

confidence: 99%

Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children

et al. 2012

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“…Effects on NO production, cytokine regulation (60) and reduced joint pain and inflammation documented in the SOJIA study (18) could be a rationale for HDACi use in osteoarthritis as well. Both types of joint diseases, RA and OA, induce severe joint bone damage with consequent clinically evident impairment of joint function.…”

Section: Influence On Bone Destructionmentioning

confidence: 99%

HDAC Inhibition in Rheumatoid Arthritis and Juvenile Idiopathic Arthritis

Vojinović

Damjanov²

2011

Mol Med

104

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“…ITF2357 (generic givinostat) is a hydroxamic acid-containing, orally active inhibitor that is anti-inflammatory in the low nanomolar range, either in vitro or in vivo (9 -16). For example, in mice with inducible (17) or spontaneous (6) diabetes, a low dose of oral ITF2357 of 1.5 mg/kg/day protected the insulin-producing islets as well as the incidence of clinical diabetes. In a Phase I trial in healthy males, oral givinostat reduced the production of proinflammatory cytokines from whole blood cultures (18).…”

Section: Itf2357 (Generic Givinostat)mentioning

confidence: 99%

Specific Inhibition of Histone Deacetylase 8 Reduces Gene Expression and Production of Proinflammatory Cytokines in Vitro and in Vivo

Fossati

Marchetti

et al. 2015

Journal of Biological Chemistry

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Background: Low concentrations of HDAC inhibitors suppress inflammation, but HDAC inhibitors are toxic at higher concentrations. Results: ITF3056 specifically inhibits HDAC8 activity and reduces proinflammatory cytokine production from human blood monocytes and in vivo but lacks cell toxicity. Conclusion: Specific inhibition of HDAC8 reduces inflammation with low cell toxicity. Significance: Inhibition of specific HDACs is preferred for treating inflammatory diseases, with fewer side effects.

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The oral histone deacetylase inhibitor ITF2357 reduces cytokine production, cytokine activities and protects islet β-cells in vivo and in vitro

Cited by 5 publications

References 0 publications

Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children

Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children

HDAC Inhibition in Rheumatoid Arthritis and Juvenile Idiopathic Arthritis

Specific Inhibition of Histone Deacetylase 8 Reduces Gene Expression and Production of Proinflammatory Cytokines in Vitro and in Vivo

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