title: Depletion of c-Rel from cytokine gene promoters is required for chromatin reassembly and termination of gene responses to T cell activation.
abstract: The role of the Nuclear Factor κB (NF-κB) transcription factor family in T cell function has been well described. The c-Rel family member is of particular importance in initiating T cell responses to antigen and regulating activation of inflammatory cytokine genes, including the Interleukin-2 (IL-2) and Granulocyte macrophage colony stimulating factor (GM-CSF) genes. c-Rel is required for chromatin remodeling of these gene promoters, which involves depletion of histones from the promoters in response to T cell activating signals. These chromatin remodeling events precede transcriptional activation of the genes. The subsequent down-regulation of cytokine gene expression is important in the termination of an immune response and here we examine this process at the murine GM-CSF and IL-2 genes. We show that the cytokine mRNA levels rapidly return to basal levels following stimulus removal and this is associated with reassembly of histones onto the promoter. Histone reassembly at the GM-CSF and IL-2 promoters occurs concomitantly with depletion of RelA, c-Rel and RNA polymerase II from the promoters. Furthermore we show that transcriptional down-regulation and chromatin reassembly is dependent on depletion of c-Rel from the nucleus, and that this is regulated by the nuclear translocation of the NF-κB inhibitor, IκBα. The nuclear activation of c-Rel therefore not only regulates the initiation of GM-CSF and IL-2 gene activation in response to T cell activation, but also the termination of these gene responses following the removal of the activating signal.
authors.affiliation: Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: Fiona S
authors.initials: FS
authors.lastname: Poke
authors.forename: William R
authors.initials: WR
authors.lastname: Upcher
authors.forename: Owen R
authors.initials: OR
authors.lastname: Sprod
authors.forename: Arabella
authors.initials: A
authors.lastname: Young
authors.forename: Kate H
authors.initials: KH
authors.lastname: Brettingham-Moore
authors.forename: Adele F
authors.initials: AF
authors.lastname: Holloway
mesh_terms: D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D015536:Down-Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021381:Protein Transport; D059748:Proteolysis; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism* / Q000502:physiology; D012319:RNA Polymerase II / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D006657:Histones; D020672:I-kappa B Proteins; D007376:Interleukin-2; C000606205:Nfkbia protein, mouse; D020569:Proto-Oncogene Proteins c-rel; D012333:RNA, Messenger; D000072000:NF-KappaB Inhibitor alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D012319:RNA Polymerase II