A novel histone deacetylase inhibitor prevents IL-1beta induced metabolic dysfunction in pancreatic beta-cells.
The histone deacetylase (HDAC) inhibitor trichostatin A (TSA) has recently been shown to inhibit deleterious effects of cytokines on beta-cells, but it is unable to protect beta-cells from death due to its own cytotoxicity. Herein, we investigated novel HDAC inhibitors for their cytoprotective effects against IL-1beta-induced damage to isolated beta-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 beta-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-1beta-mediated loss in beta-cell viability. THS-78-5 was also able to attenuate IL-1beta-induced inducible nitric oxide synthase expression and subsequent NO release. Our data also indicate that the cytoprotective properties of THS-78-5 against IL-1beta-mediated effects may, in part, be due to inhibition of IL-1beta-induced transactivation of nuclear factor kappaB (NF-kappaB) in these cells. Together, we provide evidence for a novel HDAC inhibitor with a significant potential to prevent IL-1beta-mediated effects on isolated beta-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.
Susick
Laura
L
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
Senanayake
Thulani
T
Veluthakal
Rajakrishnan
R
Woster
Patrick M
PM
Kowluru
Anjaneyulu
A
D000818:Animals; D002460:Cell Line; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D053583:Interleukin-1beta / Q000502:physiology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism
D056572:Histone Deacetylase Inhibitors; D053583:Interleukin-1beta