title: Deacetylation of C/EBPβ is required for IL-4-induced arginase-1 expression in murine macrophages.
abstract: The amount of arginine available at inflammatory loci is a limiting factor for the growth of several cells of the immune system. IL-4-induced activation of macrophages produced arginase-1, which converts arginine into ornithine, a precursor of polyamines and proline. Trichostatin A (TSA), a pan-inhibitor of histone deacetylases (HDACs), inhibited IL-4-induced arginase-1 expression. TSA showed promoter-specific effects on the IL-4-responsive genes. While TSA inhibited the expression of arginase-1, fizz1, and mrc1, other genes, such as ym,1 mgl1, and mgl2, were not affected. The inhibition of arginase-1 occurred at the transcriptional level with the inhibition of polymerase II binding to the promoter. IL-4 induced STAT6 phosphorylation and binding to DNA. These activities were not affected by TSA treatment. However, TSA inhibited C/EBPβ DNA binding. This inhibitor induced acetylation on lysine residues 215-216, which are critical for DNA binding. Finally, using macrophages from STAT6 KO mice we showed that STAT6 is required for the DNA binding of C/EBPβ. These results demonstrate that the acetylation/deacetylation balance strongly influences the expression of arginase-1, a gene of alternative activation of macrophages. These findings also provide a molecular mechanism to explain the control of gene expression through deacetylase activity.
authors.affiliation: Institute for Research in Biomedicine, Barcelona, Spain.
authors.forename: Neus
authors.initials: N
authors.lastname: Serrat
authors.forename: Selma
authors.initials: S
authors.lastname: Pereira-Lopes
authors.forename: Mònica
authors.initials: M
authors.lastname: Comalada
authors.forename: Jorge
authors.initials: J
authors.lastname: Lloberas
authors.forename: Antonio
authors.initials: A
authors.lastname: Celada
mesh_terms: D000107:Acetylation; D000818:Animals; D001119:Arginase / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000276:immunology / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010766:Phosphorylation; D012313:RNA / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D050800:STAT6 Transcription Factor / Q000276:immunology; D018709:Statistics, Nonparametric
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015847:Interleukin-4; C012589:trichostatin A; D012313:RNA; D001119:Arginase