title: Elk-3 is a KLF4-regulated gene that modulates the phagocytosis of bacteria by macrophages.
abstract: ETS family proteins play a role in immune responses. A unique member of this family, Elk-3, is a transcriptional repressor that regulates the expression of HO-1. Elk-3 is very sensitive to the effects of inflammatory mediators and is down-regulated by bacterial endotoxin (LPS). In the present study, exposure of mouse macrophages to Escherichia coli LPS resulted in decreased, full-length, and splice-variant isoforms of Elk-3. We isolated the Elk-3 promoter and demonstrated that LPS also decreased promoter activity. The Elk-3 promoter contains GC-rich regions that are putative binding sites for zinc-finger transcription factors, such as Sp1 and KLFs. Mutation of the GC-rich region from bp -613 to -603 blunted LPS-induced down-regulation of the Elk-3 promoter. Similar to the LPS response, coexpression of KLF4 led to repression of Elk-3 promoter activity, whereas coexpression of Sp1 increased activity. ChIP assays revealed that KLF4 binding to the Elk-3 promoter was increased by LPS exposure, and Sp1 binding was decreased. Thus, down-regulation of Elk-3 by bacterial LPS is regulated, in part, by the transcriptional repressor KLF4. Overexpression of Elk-3, in the presence of E. coli bacteria, resulted in decreased macrophage phagocytosis. To determine whether limited expression of HO-1 may contribute to this response, we exposed HO-1-deficient bone marrow-derived macrophages to E. coli and found a comparable reduction in bacterial phagocytosis. These data suggest that down-regulation of Elk-3 and the subsequent induction of HO-1 are important for macrophage function during the inflammatory response to infection.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Tsoyi
authors.affiliation: Department of Pediatric Newborn Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA; and.
authors.forename: Adriana M
authors.initials: AM
authors.lastname: Geldart
authors.affiliation: Department of Pediatric Newborn Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA; and.
authors.forename: Helen
authors.initials: H
authors.lastname: Christou
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, and Department of Pediatric Newborn Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, and School of Biological Sciences, University of Ulsan, South Korea.
authors.forename: Su Wol
authors.initials: SW
authors.lastname: Chung
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, and Department of Pediatric Newborn Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; mperrella@rics.bwh.harvard.edu.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Perrella
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004927:Escherichia coli Infections / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D051547:Heme Oxygenase-1 / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection
chemical_list: C086924:Elk3 protein, mouse; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D050783:Proto-Oncogene Proteins c-ets; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: gene regulation; heme oxygenase-1; infection; inflammation