RGD Reference Report - 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.

General

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.
Authors:	Lundh, M Christensen, DP Damgaard Nielsen, M Richardson, SJ Dahllof, MS Skovgaard, T Berthelsen, J Dinarello, CA Stevenazzi, A Mascagni, P Grunnet, LG Morgan, NG Mandrup-Poulsen, T
Citation:	Lundh M, etal., Diabetologia. 2012 Sep;55(9):2421-31. doi: 10.1007/s00125-012-2615-0. Epub 2012 Jul 7.
RGD ID:	9590127
Pubmed:	PMID:22772764 (View Abstract at PubMed)
DOI:	DOI:10.1007/s00125-012-2615-0 (Journal Full-text)
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 pro-inflammatory mediators Il1alpha, Il1beta, Tnfalpha or Cxcl2. HDAC3 knock-down reduced nuclear factor kappaB 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 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.

RGD Manual Disease Annotations Click to see Annotation Detail View

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
type 1 diabetes mellitus		IEP		9590127	protein:increased expression:pancreatic beta cell:	RGD
type 1 diabetes mellitus		IEP		9590127; 9590127	protein:decreased expression:pancreatic beta cell:	RGD
type 1 diabetes mellitus		ISO	HDAC1 (Homo sapiens)	9590127; 9590127	protein:increased expression:pancreatic beta cell:	RGD
type 1 diabetes mellitus		ISO	HDAC2 (Homo sapiens)	9590127; 9590127	protein:decreased expression:pancreatic beta cell:	RGD
type 1 diabetes mellitus		ISO	HDAC3 (Homo sapiens)	9590127; 9590127	protein:decreased expression:pancreatic beta cell:	RGD

Gene Ontology Annotations Click to see Annotation Detail View

Biological Process

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
negative regulation of insulin secretion		IMP		9590127		RGD
negative regulation of interleukin-1 production		IMP		9590127		RGD
negative regulation of tumor necrosis factor production		IMP		9590127		RGD
positive regulation of chemokine (C-X-C motif) ligand 2 production		IMP		9590127		RGD
positive regulation of interleukin-1 production		IMP		9590127; 9590127		RGD
positive regulation of tumor necrosis factor production		IMP		9590127; 9590127		RGD
positive regulation of type B pancreatic cell apoptotic process		IMP		9590127; 9590127		RGD

Objects Annotated

Genes (Rattus norvegicus)

Hdac1 (histone deacetylase 1)

Hdac2 (histone deacetylase 2)

Hdac3 (histone deacetylase 3)

Genes (Mus musculus)

Hdac1 (histone deacetylase 1)

Hdac2 (histone deacetylase 2)

Hdac3 (histone deacetylase 3)

Genes (Homo sapiens)

HDAC1 (histone deacetylase 1)

HDAC2 (histone deacetylase 2)

HDAC3 (histone deacetylase 3)

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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.