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.
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
Laura
L
Susick
Thulani
T
Senanayake
Rajakrishnan
R
Veluthakal
Patrick M
PM
Woster
Anjaneyulu
A
Kowluru
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