title: 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.
abstract: OBJECTIVE
  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 pro-inflammatory 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
  These data demonstrate non-redundant 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.
authors: Center for Medical Research Methodology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark. morlun@sund.ku.dk
authors: M
authors: M
authors: Lundh
authors: D P
authors: DP
authors: Christensen
authors: M
authors: M
authors: Damgaard Nielsen
authors: S J
authors: SJ
authors: Richardson
authors: M S
authors: MS
authors: Dahllöf
authors: T
authors: T
authors: Skovgaard
authors: J
authors: J
authors: Berthelsen
authors: C A
authors: CA
authors: Dinarello
authors: A
authors: A
authors: Stevenazzi
authors: P
authors: P
authors: Mascagni
authors: L G
authors: LG
authors: Grunnet
authors: N G
authors: NG
authors: Morgan
authors: T
authors: T
authors: Mandrup-Poulsen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D016207:Cytokines; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007223:Infant; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation; D000099186:Histone Deacetylase 3
chemical_list: D016207:Cytokines; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D016328:NF-kappa B; D034741:RNA, Small Interfering; D000099186:Histone Deacetylase 3; C110550:HDAC1 protein, human; C515890:Hdac1 protein, rat