The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet ß cells in vivo and in vitro
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The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet ß cells in vivo and in vitro. / Lewis, Eli C; Blaabjerg, Lykke; Størling, Joachim; Ronn, Sif G; Mascagni, Paolo; Dinarello, Charles A; Mandrup-Poulsen, Thomas.
In: Molecular Medicine, Vol. 17, No. 5-6, 05.2011, p. 369-377.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet ß cells in vivo and in vitro
AU - Lewis, Eli C
AU - Blaabjerg, Lykke
AU - Størling, Joachim
AU - Ronn, Sif G
AU - Mascagni, Paolo
AU - Dinarello, Charles A
AU - Mandrup-Poulsen, Thomas
PY - 2011/5
Y1 - 2011/5
N2 - In type 1 diabetes, inflammatory and immunocompetent cells enter the islet and produce proinflammatory cytokines such as interleukin-1ß (IL-1ß), IL-12, tumor necrosis factor-a (TNFa) and interferon-¿ (IFN¿); each contribute to ß-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-1a 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 TNFa and IFN¿ at an IC(50) of 25-50 nmol/L. In the insulin-producing INS cells challenged with the combination of IL-1ß plus IFN¿, apoptosis was reduced by 50% (P <0.01). Thus at clinically relevant doses, the orally active HDAC inhibitor ITF2357 favors ß-cell survival during inflammatory conditions.
AB - In type 1 diabetes, inflammatory and immunocompetent cells enter the islet and produce proinflammatory cytokines such as interleukin-1ß (IL-1ß), IL-12, tumor necrosis factor-a (TNFa) and interferon-¿ (IFN¿); each contribute to ß-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-1a 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 TNFa and IFN¿ at an IC(50) of 25-50 nmol/L. In the insulin-producing INS cells challenged with the combination of IL-1ß plus IFN¿, apoptosis was reduced by 50% (P <0.01). Thus at clinically relevant doses, the orally active HDAC inhibitor ITF2357 favors ß-cell survival during inflammatory conditions.
U2 - 10.2119/molmed.2010.00152
DO - 10.2119/molmed.2010.00152
M3 - Journal article
C2 - 21193899
VL - 17
SP - 369
EP - 377
JO - Molecular Medicine
JF - Molecular Medicine
SN - 0918-6557
IS - 5-6
ER -
ID: 33901375