Regulatory roles for histone deacetylation in IL-1beta-induced nitric oxide release in pancreatic beta-cells.
Histone (de)acetylases control gene transcription via modification of the chromatin structure. Herein, we investigated potential roles for histone deacetylation (or hypoacetylation) in interleukin-1beta (IL-1beta)-mediated inducible nitric oxide synthase (iNOS) and nitric oxide (NO) release in insulin-secreting INS 832/13 (INS) cells. Western blot analysis suggested localization of members of Class 1 and Class 2 families of histone deacetylases (HDACs) in these cells. Trichostatin A (TSA), a known inhibitor of HDACs, markedly reduced IL-1beta-mediated iNOS expression and NO release from these cells in a concentration-dependent manner. TSA also promoted hyperacetylation of histone H4 under conditions in which it inhibited IL-1beta-mediated effects on isolated beta cells. Rottlerin, a known inhibitor of protein kinase Cdelta, also increased histone H4 acetylation, and inhibited IL-1beta-induced iNOS expression and NO release in these cells. It appears that the putative mechanism underlying the stimulatory effects of rottlerin on acetylation status of histone H4 are distinct from the HDAC inhibitory property of TSA, since rottlerin failed to inhibit HDAC activity in nuclear extracts isolated from INS cells. These data are suggestive of potential regulatory effects of rottlerin at the level of increasing the histone acetyltransferase activity in these cells. Together our studies present the first evidence to suggest a PKCdelta-mediated signalling step, which promotes hypoacetylation of candidate histones culminating in IL-1beta-induced metabolic dysfunction of the isolated beta cell.
Susick
L
L
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.
Veluthakal
R
R
Suresh
M V
MV
Hadden
T
T
Kowluru
A
A
D000107:Acetylation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D013997:Time Factors
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D053583:Interleukin-1beta; D009569:Nitric Oxide; C012589:trichostatin A; D052247:Nitric Oxide Synthase Type II; D051745:Protein Kinase C-delta; D006655:Histone Deacetylases