title: The Fli-1 transcription factor regulates the expression of CCL5/RANTES.
abstract: The friend leukemia insertion site 1 (Fli-1) transcription factor, an Ets family member, is implicated in the pathogenesis of systemic lupus erythematosus in human patients and murine models of lupus. Lupus-prone mice with reduced Fli-1 expression have significantly less nephritis, prolonged survival, and decreased infiltrating inflammatory cells into the kidney. Inflammatory chemokines, including CCL5, are critical for attracting inflammatory cells. In this study, decreased CCL5 mRNA expression was observed in kidneys of lupus-prone NZM2410 mice with reduced Fli-1 expression. CCL5 protein expression was significantly decreased in endothelial cells transfected with Fli-1-specific small interfering RNA compared with controls. Fli-1 binds to endogenous Ets binding sites in the distal region of the CCL5 promoter. Transient transfection assays demonstrate that Fli-1 drives transcription from the CCL5 promoter in a dose-dependent manner. Both Ets1, another Ets family member, and Fli-1 drive transcription from the CCL5 promoter, although Fli-1 transactivation was significantly stronger. Ets1 acts as a dominant-negative transcription factor for Fli-1, indicating that they may have at least one DNA binding site in common. Systematic deletion of DNA binding sites demonstrates the importance of the sites located within a 225-bp region of the promoter. Mutation of the Fli-1 DNA binding domain significantly reduces transactivation of the CCL5 promoter by Fli-1. We identified a novel regulator of transcription for CCL5. These results suggest that Fli-1 is a novel and critical regulator of proinflammatory chemokines and affects the pathogenesis of disease through the regulation of factors that recruit inflammatory cells to sites of inflammation.
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Mara L
authors.initials: ML
authors.lastname: Lennard Richard
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Shuzo
authors.initials: S
authors.lastname: Sato
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Eiji
authors.initials: E
authors.lastname: Suzuki
authors.affiliation: Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403.
authors.forename: Sarah
authors.initials: S
authors.lastname: Williams
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425; and Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403.
authors.forename: Tamara K
authors.initials: TK
authors.lastname: Nowling
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425; and Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403 zhangjo@musc.edu.
authors.forename: Xian K
authors.initials: XK
authors.lastname: Zhang
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics*; D004247:DNA / Q000737:chemistry* / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007668:Kidney / Q000166:cytology / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009393:Nephritis / Q000235:genetics; D011401:Promoter Regions, Genetic; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics; D051789:Proto-Oncogene Protein c-fli-1 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D015533:Transcriptional Activation / Q000235:genetics*; D014162:Transfection
chemical_list: C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D004268:DNA-Binding Proteins; C494042:Ets1 protein, mouse; C497426:Fli1 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1; D051789:Proto-Oncogene Protein c-fli-1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D004247:DNA
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