title: Fli-1 controls transcription from the MCP-1 gene promoter, which may provide a novel mechanism for chemokine and cytokine activation.
abstract: Regulation of proinflammatory cytokines and chemokines is a primary role of the innate immune response. MCP-1 is a chemokine that recruits immune cells to sites of inflammation. Expression of MCP-1 is reduced in primary kidney endothelial cells from mice with a heterozygous knockout of the Fli-1 transcription factor. Fli-1 is a member of the Ets family of transcription factors, which are evolutionarily conserved across several organisms including Drosophilla, Xenopus, mouse and human. Ets family members bind DNA through a consensus sequence GGAA/T, or Ets binding site (EBS). Fli-1 binds to EBSs within the endogenous MCP-1 promoter by ChIP assay. In this study, transient transfection assays indicate that the Fli-1 gene actively promotes transcription from the MCP-1 gene promoter in a dose-dependent manner. Mutation of the DNA binding domain of Fli-1 demonstrated that Fli-1 activates transcription of MCP-1 both directly, by binding to the promoter, and indirectly, likely through interactions with other transcription factors. Another Ets transcription factor, Ets-1, was also tested, but failed to promote transcription. While Ets-1 failed to drive transcription independently, a weak synergistic activation of the MCP-1 promoter was observed between Ets-1 and Fli-1. In addition, Fli-1 and the NFκB family member p65 were found to interact synergistically to activate transcription from the MCP-1 promoter, while Sp1 and p50 inhibit this interaction. Deletion studies identified that EBSs in the distal and proximal MCP-1 promoter are critical for Fli-1 activation from the MCP-1 promoter. Together, these results demonstrate that Fli-1 is a novel regulator of the proinflammatory chemokine MCP-1, that interacts with other transcription factors to form a complex transcriptional mechanism for the activation of MCP-1 and mediation of the inflammatory response.
authors.affiliation: Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Mara L
authors.initials: ML
authors.lastname: Lennard Richard
authors.affiliation: Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC 29425, USA; Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403, USA.
authors.forename: Tamara K
authors.initials: TK
authors.lastname: Nowling
authors.affiliation: Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Brandon
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Watson
authors.affiliation: Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC 29425, USA; Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403, USA. Electronic address: zhangjo@musc.edu.
authors.forename: Xian K
authors.initials: XK
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D018932:Chemokine CCL2 / Q000235:genetics*; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D018932:Chemokine CCL2; D051789:Proto-Oncogene Protein c-fli-1; D016329:Sp1 Transcription Factor; D051996:Transcription Factor RelA
keywords: Chemokines; Fli-1; Gene regulation; Inflammation; MCP-1; Transcriptional factors
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