A novel histone deacetylase inhibitor prevents IL‐1β induced metabolic dysfunction in pancreatic β‐cells

The histone deacetylase (HDAC) inhibitor trichostatin A (TSA) has recently been shown to inhibit deleterious effects of cytokines on beta-cells, but it is unable to protect beta-cells from death due to its own cytotoxicity. Herein, we investigated novel HDAC inhibitors for their cytoprotective effects against IL-1beta-induced damage to isolated beta-cells. We report that three novel compounds (THS-73-44, THS-72-5 and THS-78-5) significantly inhibited HDAC activity and increased the acetylation of histone H4 in isolated beta-cells. Further, these compounds exerted no toxic effects on metabolic cell viability in these cells. However, among the three compounds tested, only THS-78-5 protected against IL-1beta-mediated loss in beta-cell viability. THS-78-5 was also able to attenuate IL-1beta-induced inducible nitric oxide synthase expression and subsequent NO release. Our data also indicate that the cytoprotective properties of THS-78-5 against IL-1beta-mediated effects may, in part, be due to inhibition of IL-1beta-induced transactivation of nuclear factor kappaB (NF-kappaB) in these cells. Together, we provide evidence for a novel HDAC inhibitor with a significant potential to prevent IL-1beta-mediated effects on isolated beta-cells. Potential implications of these findings in the development of novel therapeutics to prevent deleterious effects of cytokines and the onset of autoimmune diabetes are discussed.

[1]  A. Mirsky,et al.  ACETYLATION AND METHYLATION OF HISTONES AND THEIR POSSIBLE ROLE IN THE REGULATION OF RNA SYNTHESIS. , 1964, Proceedings of the National Academy of Sciences of the United States of America.

[2]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[3]  E. Cagliero,et al.  Interleukin‐1β induces the expression of an isoform of nitric oxide synthase in insulin‐producing cells, which is similar to that observed in activated macrophages , 1992 .

[4]  N. Welsh,et al.  Cytokines activate the nuclear factor kappa B (NF-kappa B) and induce nitric oxide production in human pancreatic islets. , 1996, FEBS letters.

[5]  N. Welsh,et al.  Cytokines activate the nuclear factor κB (NF‐κB) and induce nitric oxide production in human pancreatic islets , 1996 .

[6]  W. Suarez-Pinzon,et al.  Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus. , 1998, Biochemical pharmacology.

[7]  C. Fiorentini,et al.  Positive modulation by Ras of interleukin-1β-mediated nitric oxide generation in insulin-secreting clonal β (HIT-T15) cells , 2001 .

[8]  C. Fiorentini,et al.  Positive modulation by Ras of interleukin-1beta-mediated nitric oxide generation in insulin-secreting clonal beta (HIT-T15) cells. , 2001, Biochemical pharmacology.

[9]  T. Mandrup-Poulsen,et al.  A choice of death – the signal-transduction of immune-mediated beta-cell apoptosis , 2001, Diabetologia.

[10]  Craig L. Peterson,et al.  Chromatin Higher Order Folding--Wrapping up Transcription , 2002, Science.

[11]  Wenzheng Zhang,et al.  Histone deacetylases augment cytokine induction of the iNOS gene. , 2002, Journal of the American Society of Nephrology : JASN.

[12]  C. Peterson,et al.  Molecular biology. Chromatin higher order folding--wrapping up transcription. , 2002, Science.

[13]  P. Becker,et al.  Histone acetylation: a switch between repressive and permissive chromatin , 2002, EMBO reports.

[14]  A. Kowluru,et al.  Novel roles for palmitoylation of Ras in IL-1β-induced nitric oxide release and caspase 3 activation in insulin-secreting β cells , 2003 .

[15]  C. M. Pieper,et al.  Spatial distribution and temporal onset of NF-kB activation and inducible nitric oxide synthase within pancreatic islets in the pre-diabetic stage of genetic, diabetic-prone BB rats: Attenuation by drug intervention decreases inflammatory cell infiltration and incidence of diabetes , 2003, Inflammation Research.

[16]  R. Mirmira,et al.  Covalent Histone Modifications Underlie the Developmental Regulation of Insulin Gene Transcription in Pancreatic β Cells* , 2003, Journal of Biological Chemistry.

[17]  A. Mosley,et al.  Glucose Regulates Insulin Gene Transcription by Hyperacetylation of Histone H4* , 2003, Journal of Biological Chemistry.

[18]  T. Mandrup-Poulsen,et al.  The role of interleukin-1 in the pathogenesis of IDDM , 1996, Diabetologia.

[19]  A. Mosley,et al.  Glucose regulation of insulin gene expression requires the recruitment of p300 by the beta-cell-specific transcription factor Pdx-1. , 2004, Molecular endocrinology.

[20]  Y. E. Chin,et al.  Stat3 Dimerization Regulated by Reversible Acetylation of a Single Lysine Residue , 2005, Science.

[21]  M. Quon,et al.  Essential role for membrane lipid rafts in interleukin-1beta-induced nitric oxide release from insulin-secreting cells: potential regulation by caveolin-1+. , 2005, Diabetes.

[22]  G. Stephanopoulos,et al.  Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis , 2005, Journal of Neuroimmunology.

[23]  N. Colburn,et al.  Histone Deacetylase Inhibition Down-Regulates Cyclin D1 Transcription by Inhibiting Nuclear Factor-κB/p65 DNA Binding , 2005, Molecular Cancer Research.

[24]  F. Blanchard,et al.  Histone deacetylase inhibitors: new drugs for the treatment of inflammatory diseases? , 2005, Drug discovery today.

[25]  P. Woster,et al.  Alkyl-substituted polyaminohydroxamic acids: a novel class of targeted histone deacetylase inhibitors. , 2005, Journal of medicinal chemistry.

[26]  Jianyuan Luo,et al.  Activation of Stat3 Sequence-specific DNA Binding and Transcription by p300/CREB-binding Protein-mediated Acetylation* , 2005, Journal of Biological Chemistry.

[27]  Lili Huang,et al.  Targeting histone deacetylases for the treatment of cancer and inflammatory diseases , 2006, Journal of cellular physiology.

[28]  Zhi-yuan Yu,et al.  Targeted histone H4 acetylation via phosphoinositide 3-kinase- and p70s6-kinase-dependent pathways inhibits iNOS induction in mesangial cells. , 2006, American journal of physiology. Renal physiology.

[29]  S. G. Rønn,et al.  Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells , 2007, Diabetologia.

[30]  D. Schuppan,et al.  Antiproliferative and proapoptotic effects of histone deacetylase inhibitors on gastrointestinal neuroendocrine tumor cells. , 2006, Endocrine-related cancer.

[31]  M. Fresno,et al.  Regulation of Inducible Nitric Oxide Synthase Expression by Viral A238L-Mediated Inhibition of p65/RelA Acetylation and p300 Transactivation , 2006, Journal of Virology.

[32]  D. Schrump,et al.  Rapid and profound potentiation of Apo2L/TRAIL-mediated cytotoxicity and apoptosis in thoracic cancer cells by the histone deacetylase inhibitor Trichostatin A: the essential role of the mitochondria-mediated caspase activation cascade , 2006, Apoptosis.

[33]  N. Guseva,et al.  TSA-induced cell death in prostate cancer cell lines is caspase-2 dependent and involves the PIDDosome , 2006, Cancer biology & therapy.

[34]  Yingjie Zhang,et al.  The mouse C/EBPδ gene promoter is regulated by STAT3 and Sp1 transcriptional activators, chromatin remodeling and c‐Myc repression , 2007, Journal of cellular biochemistry.

[35]  A. Kowluru,et al.  Dominant-Negative α-Subunit of Farnesyl- and Geranyltransferase Inhibits Glucose-Stimulated, but Not KCl-Stimulated, Insulin Secretion in INS 832/13 Cells , 2007, Diabetes.

[36]  A. Kowluru,et al.  Biologically active lipids promote trafficking and membrane association of Rac1 in insulin-secreting INS 832/13 cells. , 2007, American journal of physiology. Cell physiology.

[37]  R. Baron,et al.  Anti‐rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen‐induced arthritis in rodents , 2007, British journal of pharmacology.

[38]  H. Moch,et al.  Histone deacetylase/acetylase activity in total synovial tissue derived from rheumatoid arthritis and osteoarthritis patients. , 2007, Arthritis and rheumatism.

[39]  C. Van Lint,et al.  Histone deacetylase inhibitor trichostatin A sustains sodium pervanadate-induced NF-kappaB activation by delaying IkappaBalpha mRNA resynthesis: comparison with tumor necrosis factor alpha. , 2007, The Journal of biological chemistry.

[40]  P. Bitterman,et al.  Histone Deacetylase Inhibitors Suppress TF-κB-dependent Agonist-driven Tissue Factor Expression in Endothelial Cells and Monocytes* , 2007, Journal of Biological Chemistry.

[41]  P. Finn,et al.  Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. , 2008, The Biochemical journal.

[42]  M. V. Suresh,et al.  Regulatory roles for histone deacetylation in IL-1β-induced nitric oxide release in pancreatic β-cells , 2007, Journal of cellular and molecular medicine.

[43]  P. Woster,et al.  Polyaminohydroxamic acids and polyaminobenzamides as isoform selective histone deacetylase inhibitors. , 2008, Journal of medicinal chemistry.