The lysine deacetylase inhibitor givinostat inhibits ß-cell IL-1ß induced IL-1ß transcription and processing
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Islets |
Volume | 4 |
Issue number | 6 |
Pages (from-to) | 417-22 |
Number of pages | 6 |
ISSN | 1938-2014 |
DOIs | |
Publication status | Published - 1 Nov 2012 |
ID: 45238727