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 journal › Journal article › Research › peer-review
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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