The lysine deacetylase inhibitor givinostat inhibits ß-cell IL-1ß induced IL-1ß transcription and processing

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The lysine deacetylase inhibitor givinostat inhibits ß-cell IL-1ß induced IL-1ß transcription and processing. / Dahllöf, Mattias Salling; Christensen, Dan P; Lundh, Morten; Dinarello, Charles A; Mascagni, Paolo; Grunnet, Lars G; Mandrup-Poulsen, Thomas.

In: Islets, Vol. 4, No. 6, 01.11.2012, p. 417-22.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Dahllöf, MS, Christensen, DP, Lundh, M, Dinarello, CA, Mascagni, P, Grunnet, LG & Mandrup-Poulsen, T 2012, 'The lysine deacetylase inhibitor givinostat inhibits ß-cell IL-1ß induced IL-1ß transcription and processing', Islets, vol. 4, no. 6, pp. 417-22. https://doi.org/10.4161/isl.23541

APA

Dahllöf, M. S., Christensen, D. P., Lundh, M., Dinarello, C. A., Mascagni, P., Grunnet, L. G., & Mandrup-Poulsen, T. (2012). The lysine deacetylase inhibitor givinostat inhibits ß-cell IL-1ß induced IL-1ß transcription and processing. Islets, 4(6), 417-22. https://doi.org/10.4161/isl.23541

Vancouver

Dahllöf MS, Christensen DP, Lundh M, Dinarello CA, Mascagni P, Grunnet LG et al. The lysine deacetylase inhibitor givinostat inhibits ß-cell IL-1ß induced IL-1ß transcription and processing. Islets. 2012 Nov 1;4(6):417-22. https://doi.org/10.4161/isl.23541

Author

Dahllöf, Mattias Salling ; Christensen, Dan P ; Lundh, Morten ; Dinarello, Charles A ; Mascagni, Paolo ; Grunnet, Lars G ; Mandrup-Poulsen, Thomas. / The lysine deacetylase inhibitor givinostat inhibits ß-cell IL-1ß induced IL-1ß transcription and processing. In: Islets. 2012 ; Vol. 4, No. 6. pp. 417-22.

Bibtex

@article{31cd36820c47489c8ad21d7a4fbc3141,
title = "The lysine deacetylase inhibitor givinostat inhibits {\ss}-cell IL-1{\ss} induced IL-1{\ss} transcription and processing",
abstract = "Aims: Pro-inflammatory cytokines and chemokines, in particular IL-1{\ss}, IFN¿, and CXCL10, contribute to {\ss}-cell failure and loss in DM via IL-1R, IFN¿R, and TLR4 signaling. IL-1 signaling deficiency reduces diabetes incidence, islet IL-1{\ss} secretion, and hyperglycemia in animal models of diabetes. Further, IL-1R antagonism improves normoglycemia and {\ss}-cell function in type 2 diabetic patients. Inhibition of lysine deacetylases (KDACi) counteracts {\ss}-cell toxicity induced by the combination of IL-1 and IFN¿ and reduces diabetes incidence in non-obese diabetic (NOD) mice. We hypothesized that KDACi breaks an autoinflammatory circuit by differentially preventing {\ss}-cell expression of the {\ss}-cell toxic inflammatory molecules IL-1{\ss} and CXCL10 induced by single cytokines. Results: CXCL10 did not induce transcription of IL-1{\ss} mRNA. IL-1{\ss} induced {\ss}-cell IL-1{\ss} mRNA and both IL-1{\ss} and IFN¿ individually induced Cxcl10 mRNA transcription. Givinostat inhibited IL-1{\ss}-induced IL-1{\ss} mRNA expression in INS-1 and rat islets and IL-1{\ss} processing in INS-1 cells. Givinostat also reduced IFN¿ induced Cxcl10 transcription in INS-1 cells but not in rat islets, while IL-1{\ss} induced Cxcl10 transcription was unaffected in both. Materials and Methods: INS-1 cells and rat islets of Langerhans were exposed to IL-1{\ss}, IFN¿ or CXCL10 in the presence or absence of KDACi (givinostat). Cytokine and chemokine mRNA expressions were quantified by real-time qPCR, and IL-1{\ss} processing by western blotting of cell lysates. Conclusion/Interpretation: Inhibition of {\ss}-cell IL-1{\ss} expression and processing and Cxcl10 transcription contributes to the {\ss}-cell protective actions of KDACi. In vitro {\ss}-cell destructive effects of CXCL10 are not mediated via IL-1{\ss} transcription. The differential proinflammatory actions of KDACs may be attractive novel drug targets in DM.",
author = "Dahll{\"o}f, {Mattias Salling} and Christensen, {Dan P} and Morten Lundh and Dinarello, {Charles A} and Paolo Mascagni and Grunnet, {Lars G} and Thomas Mandrup-Poulsen",
year = "2012",
month = nov,
day = "1",
doi = "10.4161/isl.23541",
language = "English",
volume = "4",
pages = "417--22",
journal = "Islets",
issn = "1938-2014",
publisher = "Taylor & Francis",
number = "6",

}

RIS

TY - JOUR

T1 - The lysine deacetylase inhibitor givinostat inhibits ß-cell IL-1ß induced IL-1ß transcription and processing

AU - Dahllöf, Mattias Salling

AU - Christensen, Dan P

AU - Lundh, Morten

AU - Dinarello, Charles A

AU - Mascagni, Paolo

AU - Grunnet, Lars G

AU - Mandrup-Poulsen, Thomas

PY - 2012/11/1

Y1 - 2012/11/1

N2 - Aims: Pro-inflammatory cytokines and chemokines, in particular IL-1ß, IFN¿, and CXCL10, contribute to ß-cell failure and loss in DM via IL-1R, IFN¿R, and TLR4 signaling. IL-1 signaling deficiency reduces diabetes incidence, islet IL-1ß secretion, and hyperglycemia in animal models of diabetes. Further, IL-1R antagonism improves normoglycemia and ß-cell function in type 2 diabetic patients. Inhibition of lysine deacetylases (KDACi) counteracts ß-cell toxicity induced by the combination of IL-1 and IFN¿ and reduces diabetes incidence in non-obese diabetic (NOD) mice. We hypothesized that KDACi breaks an autoinflammatory circuit by differentially preventing ß-cell expression of the ß-cell toxic inflammatory molecules IL-1ß and CXCL10 induced by single cytokines. Results: CXCL10 did not induce transcription of IL-1ß mRNA. IL-1ß induced ß-cell IL-1ß mRNA and both IL-1ß and IFN¿ individually induced Cxcl10 mRNA transcription. Givinostat inhibited IL-1ß-induced IL-1ß mRNA expression in INS-1 and rat islets and IL-1ß processing in INS-1 cells. Givinostat also reduced IFN¿ induced Cxcl10 transcription in INS-1 cells but not in rat islets, while IL-1ß induced Cxcl10 transcription was unaffected in both. Materials and Methods: INS-1 cells and rat islets of Langerhans were exposed to IL-1ß, IFN¿ or CXCL10 in the presence or absence of KDACi (givinostat). Cytokine and chemokine mRNA expressions were quantified by real-time qPCR, and IL-1ß processing by western blotting of cell lysates. Conclusion/Interpretation: Inhibition of ß-cell IL-1ß expression and processing and Cxcl10 transcription contributes to the ß-cell protective actions of KDACi. In vitro ß-cell destructive effects of CXCL10 are not mediated via IL-1ß transcription. The differential proinflammatory actions of KDACs may be attractive novel drug targets in DM.

AB - Aims: Pro-inflammatory cytokines and chemokines, in particular IL-1ß, IFN¿, and CXCL10, contribute to ß-cell failure and loss in DM via IL-1R, IFN¿R, and TLR4 signaling. IL-1 signaling deficiency reduces diabetes incidence, islet IL-1ß secretion, and hyperglycemia in animal models of diabetes. Further, IL-1R antagonism improves normoglycemia and ß-cell function in type 2 diabetic patients. Inhibition of lysine deacetylases (KDACi) counteracts ß-cell toxicity induced by the combination of IL-1 and IFN¿ and reduces diabetes incidence in non-obese diabetic (NOD) mice. We hypothesized that KDACi breaks an autoinflammatory circuit by differentially preventing ß-cell expression of the ß-cell toxic inflammatory molecules IL-1ß and CXCL10 induced by single cytokines. Results: CXCL10 did not induce transcription of IL-1ß mRNA. IL-1ß induced ß-cell IL-1ß mRNA and both IL-1ß and IFN¿ individually induced Cxcl10 mRNA transcription. Givinostat inhibited IL-1ß-induced IL-1ß mRNA expression in INS-1 and rat islets and IL-1ß processing in INS-1 cells. Givinostat also reduced IFN¿ induced Cxcl10 transcription in INS-1 cells but not in rat islets, while IL-1ß induced Cxcl10 transcription was unaffected in both. Materials and Methods: INS-1 cells and rat islets of Langerhans were exposed to IL-1ß, IFN¿ or CXCL10 in the presence or absence of KDACi (givinostat). Cytokine and chemokine mRNA expressions were quantified by real-time qPCR, and IL-1ß processing by western blotting of cell lysates. Conclusion/Interpretation: Inhibition of ß-cell IL-1ß expression and processing and Cxcl10 transcription contributes to the ß-cell protective actions of KDACi. In vitro ß-cell destructive effects of CXCL10 are not mediated via IL-1ß transcription. The differential proinflammatory actions of KDACs may be attractive novel drug targets in DM.

U2 - 10.4161/isl.23541

DO - 10.4161/isl.23541

M3 - Journal article

C2 - 23486342

VL - 4

SP - 417

EP - 422

JO - Islets

JF - Islets

SN - 1938-2014

IS - 6

ER -

ID: 45238727