Inhibition of histone deacetylation enhances endotoxin-stimulated transcription but does not reverse endotoxin tolerance.
Covalent modification of histones and the subsequent remodeling of chromatin have emerged as important mechanisms in regulating gene expression. In particular, recent identification of the enzyme families responsible for the steady-state balance of histone acetylation has served to redefine our understanding of these modifications as fundamental biochemical processes regulating transcription. Current evidence suggests that histone acetylation correlates positively with gene activation, while histone deacetylation acts to repress transcription. In this study, we examined the role of histone modification in the inflammatory response to endotoxin. We focused on the endotoxin-stimulated expression of the interleukin-1beta promoter and tested the hypotheses that persistent histone deacetylation was responsible for the decreased expression of this promoter observed after prolonged exposure to endotoxin, a manifestation of a phenomenon known as endotoxin tolerance. We found that histone deacetylase inhibitors enhanced endotoxin-stimulated transcription; however, deacetylation inhibitors could neither block the development of tolerance nor restore endotoxin sensitivity in a tolerant cell. Deacetylase inhibitors could not restore LPS-mediated transcription in tolerant cells. These results show that histone acetylation/deacetylation regulates, at least in part, the endotoxin-induced expression of inflammatory genes and that repressed transcription observed in endotoxin tolerance is not caused by enhanced activity of histone deacetylases.
Yoza
Barbara K
BK
Department of Medicine, Section on Infectious Diseases, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. byoza@wfubmc.edu
Hu
Jean Y-Q
JY
McCall
Charles E
CE
D015152:Blotting, Northern; D002478:Cells, Cultured; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D003640:Dealkylation; D004731:Endotoxins / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006207:Half-Life; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000633:toxicity; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation; D014162:Transfection
D002843:Chromatin; D004731:Endotoxins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger