Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Islets. 2012 Nov-Dec;4(6):417-22. doi: 10.4161/isl.23541.

The lysine deacetylase inhibitor Givinostat inhibits β-cell IL-1β induced IL-1β transcription and processing.

Author information

  • 1Endocrinology Research Section, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

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.

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.

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.

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.

KEYWORDS:

apoptosis; chemokines; cytokines; diabetes mellitus; histone deacetylases; inflammation

PMID:
23486342
[PubMed - indexed for MEDLINE]
PMCID:
PMC3605170
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Landes Bioscience Icon for PubMed Central
    Loading ...
    Write to the Help Desk