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

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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. / Lundh, M; Christensen, D P; Damgaard Nielsen, M; Richardson, S J; Dahllöf, M S; Skovgaard, T; Berthelsen, J; Dinarello, C A; Stevenazzi, A; Mascagni, P; Grunnet, L G; Morgan, N G; Mandrup-Poulsen, Thomas.

In: Diabetologia, Vol. 55, No. 9, 2012, p. 2421-31.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Lundh, M, Christensen, DP, Damgaard Nielsen, M, Richardson, SJ, Dahllöf, MS, Skovgaard, T, Berthelsen, J, Dinarello, CA, Stevenazzi, A, Mascagni, P, Grunnet, LG, Morgan, NG & Mandrup-Poulsen, T 2012, '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', Diabetologia, vol. 55, no. 9, pp. 2421-31. https://doi.org/10.1007/s00125-012-2615-0

APA

Lundh, M., Christensen, D. P., Damgaard Nielsen, M., Richardson, S. J., Dahllöf, M. S., Skovgaard, T., ... Mandrup-Poulsen, T. (2012). 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. Diabetologia, 55(9), 2421-31. https://doi.org/10.1007/s00125-012-2615-0

Vancouver

Lundh M, Christensen DP, Damgaard Nielsen M, Richardson SJ, Dahllöf MS, Skovgaard T et al. 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. Diabetologia. 2012;55(9):2421-31. https://doi.org/10.1007/s00125-012-2615-0

Author

Lundh, M ; Christensen, D P ; Damgaard Nielsen, M ; Richardson, S J ; Dahllöf, M S ; Skovgaard, T ; Berthelsen, J ; Dinarello, C A ; Stevenazzi, A ; Mascagni, P ; Grunnet, L G ; Morgan, N G ; Mandrup-Poulsen, Thomas. / 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. In: Diabetologia. 2012 ; Vol. 55, No. 9. pp. 2421-31.

Bibtex

@article{8f7203d62f444e26979d7b8224ce0e3a,
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 = "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 Il1a, Il1{\ss}, Tnfa or Cxcl2. HDAC3 knock-down reduced nuclear factor ¿B 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.",
author = "M Lundh and Christensen, {D P} and {Damgaard Nielsen}, M and Richardson, {S J} and Dahll{\"o}f, {M S} and T Skovgaard and J Berthelsen and Dinarello, {C A} and A Stevenazzi and P Mascagni and Grunnet, {L G} and Morgan, {N G} and Thomas Mandrup-Poulsen",
year = "2012",
doi = "10.1007/s00125-012-2615-0",
language = "English",
volume = "55",
pages = "2421--31",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer",
number = "9",

}

RIS

TY - JOUR

T1 - 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

AU - Lundh, M

AU - Christensen, D P

AU - Damgaard Nielsen, M

AU - Richardson, S J

AU - Dahllöf, M S

AU - Skovgaard, T

AU - Berthelsen, J

AU - Dinarello, C A

AU - Stevenazzi, A

AU - Mascagni, P

AU - Grunnet, L G

AU - Morgan, N G

AU - Mandrup-Poulsen, Thomas

PY - 2012

Y1 - 2012

N2 - 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 Il1a, Il1ß, Tnfa or Cxcl2. HDAC3 knock-down reduced nuclear factor ¿B 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.

AB - 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 Il1a, Il1ß, Tnfa or Cxcl2. HDAC3 knock-down reduced nuclear factor ¿B 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.

U2 - 10.1007/s00125-012-2615-0

DO - 10.1007/s00125-012-2615-0

M3 - Journal article

VL - 55

SP - 2421

EP - 2431

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 9

ER -

ID: 38412430