title: The response of secondary genes to lipopolysaccharides in macrophages depends on histone deacetylase and phosphorylation of C/EBPβ.
abstract: LPS induces the expression of NO synthase 2 (nos2) in macrophages. The expression of this molecule is one of the hallmarks of classical activation. In this paper, we describe that trichostatin A (TSA), which inhibits deacetylase activity, blocks LPS-dependent nos2 expression. TSA specifically inhibits LPS-dependent genes of secondary response, which require new protein synthesis for their induction but not those belonging to the primary response, which do not depend on this process. Deacetylase activity acts at the transcriptional level because RNA polymerase II was not bound after LPS stimulus when we added TSA. A link between the global acetylation caused by HDAC inhibitor and gene promoter recruitment of CDK8 was found. This Mediator complex subunit associates with Med 12, Med13, and cyclin C to form a submodule that is a transcriptional negative regulator. We also found that TSA reduces C/EBPβ phosphorylation without affecting its binding to DNA. Taken together, these results shed light on the molecular mechanisms involved in the transcriptional regulation of LPS-treated macrophages and on how TSA targets critical LPS-induced genes, such as nos2 and tnf-α, in inflammatory macrophage response.
authors.affiliation: Macrophage Biology Group, Department of Physiology and Immunology, University of Barcelona, E-08028 Barcelona, Spain.
authors.forename: Neus
authors.initials: N
authors.lastname: Serrat
authors.forename: Carlos
authors.initials: C
authors.lastname: Sebastian
authors.forename: Selma
authors.initials: S
authors.lastname: Pereira-Lopes
authors.forename: Lorena
authors.initials: L
authors.lastname: Valverde-Estrella
authors.forename: Jorge
authors.initials: J
authors.lastname: Lloberas
authors.forename: Antonio
authors.initials: A
authors.lastname: Celada
mesh_terms: D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D056850:Cyclin-Dependent Kinase 8 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D023061:Gene Order; D020868:Gene Silencing; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012319:RNA Polymerase II / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D035181:TATA-Box Binding Protein / Q000378:metabolism; D061785:Transcription Initiation, Genetic; D014158:Transcription, Genetic / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D016328:NF-kappa B; D035181:TATA-Box Binding Protein; C012589:trichostatin A; D052247:Nitric Oxide Synthase Type II; D056850:Cyclin-Dependent Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; D012319:RNA Polymerase II; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases