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- Title
A novel histone deacetylase inhibitor prevents IL-1β induced metabolic dysfunction in pancreatic β-cells.
- Authors
Susick, Laura; Senanayake, Thulani; Veluthakal, Rajakrishnan; Woster, Patrick M.; Kowluru, Anjaneyulu
- Abstract
The histone deacetylase (HDAC) inhibitor trichostatin A (TSA) has recently been shown to inhibit deleterious effects of cytokines on β-cells, but it is unable to protect β-cells from death due to its own cytotoxicity. Herein, we investigated novel HDAC inhibitors for their cytoprotective effects against IL-1β-induced damage to isolated β-cells. We report that three novel compounds (THS-73–44, THS-72–5 and THS-78–5) significantly inhibited HDAC activity and increased the acetylation of histone H4 in isolated β-cells. Further, these compounds exerted no toxic effects on metabolic cell viability in these cells. However, among the three compounds tested, only THS-78–5 protected against IL-1β-mediated loss in β-cell viability. THS-78–5 was also able to attenuate IL-1β-induced inducible nitric oxide synthase expression and subsequent NO release. Our data also indicate that the cytoprotective properties of THS-78–5 against IL-1β-mediated effects may, in part, be due to inhibition of IL-1β-induced transactivation of nuclear factor κB (NF-κB) in these cells. Together, we provide evidence for a novel HDAC inhibitor with a significant potential to prevent IL-1β-mediated effects on isolated β-cells. Potential implications of these findings in the development of novel therapeutics to prevent deleterious effects of cytokines and the onset of autoimmune diabetes are discussed.
- Subjects
HISTONE deacetylase; CYTOKINES; CELL-mediated cytotoxicity; METABOLISM; AUTOIMMUNE diseases; GENE expression
- Publication
Journal of Cellular & Molecular Medicine, 2009, Vol 13, Issue 8b, p1877
- ISSN
1582-1838
- Publication type
Article
- DOI
10.1111/j.1582-4934.2008.00672.x