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The lysine deacetylase inhibitor Givinostat inhibits β-cell IL-1β induced IL-1β transcription and processing.
- Source :
-
Islets [Islets] 2012 Nov-Dec; Vol. 4 (6), pp. 417-22. - Publication Year :
- 2012
-
Abstract
- Aims: Pro-inflammatory cytokines and chemokines, in particular IL-1β, IFNγ, and CXCL10, contribute to β-cell failure and loss in DM via IL-1R, IFNγR, and TLR4 signaling. IL-1 signaling deficiency reduces diabetes incidence, islet IL-1β secretion, and hyperglycemia in animal models of diabetes. Further, IL-1R antagonism improves normoglycemia and β-cell function in type 2 diabetic patients. Inhibition of lysine deacetylases (KDACi) counteracts β-cell toxicity induced by the combination of IL-1 and IFNγ and reduces diabetes incidence in non-obese diabetic (NOD) mice. We hypothesized that KDACi breaks an autoinflammatory circuit by differentially preventing β-cell expression of the β-cell toxic inflammatory molecules IL-1β and CXCL10 induced by single cytokines.<br />Results: CXCL10 did not induce transcription of IL-1β mRNA. IL-1β induced β-cell IL-1β mRNA and both IL-1β and IFNγ individually induced Cxcl10 mRNA transcription. Givinostat inhibited IL-1β-induced IL-1β mRNA expression in INS-1 and rat islets and IL-1β processing in INS-1 cells. Givinostat also reduced IFNγ induced Cxcl10 transcription in INS-1 cells but not in rat islets, while IL-1β induced Cxcl10 transcription was unaffected in both.<br />Materials and Methods: INS-1 cells and rat islets of Langerhans were exposed to IL-1β, IFNγ or CXCL10 in the presence or absence of KDACi (givinostat). Cytokine and chemokine mRNA expressions were quantified by real-time qPCR, and IL-1β processing by western blotting of cell lysates.<br />Conclusion/interpretation: Inhibition of β-cell IL-1β expression and processing and Cxcl10 transcription contributes to the β-cell protective actions of KDACi. In vitro β-cell destructive effects of CXCL10 are not mediated via IL-1β transcription. The differential proinflammatory actions of KDACs may be attractive novel drug targets in DM.
- Subjects :
- Animals
Chemokine CXCL10 biosynthesis
Chemokine CXCL10 genetics
Diabetes Mellitus enzymology
Diabetes Mellitus genetics
Humans
Insulin-Secreting Cells enzymology
Insulin-Secreting Cells immunology
Interferon-gamma biosynthesis
Interferon-gamma genetics
Interleukin-1beta genetics
RNA, Messenger chemistry
RNA, Messenger genetics
Rats
Rats, Wistar
Real-Time Polymerase Chain Reaction
Transcription, Genetic drug effects
Carbamates pharmacology
Diabetes Mellitus immunology
Histone Deacetylase Inhibitors pharmacology
Insulin-Secreting Cells drug effects
Interleukin-1beta biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1938-2022
- Volume :
- 4
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Islets
- Publication Type :
- Academic Journal
- Accession number :
- 23486342
- Full Text :
- https://doi.org/10.4161/isl.23541