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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.
Bradshaw,
A role for Fli-1 in B cell proliferation: implications for SLE pathogenesis.
2008, Pubmed
Bradshaw,
A role for Fli-1 in B cell proliferation: implications for SLE pathogenesis.
2008,
Pubmed Chen,
Isolation and characterization of five Drosophila genes that encode an ets-related DNA binding domain.
1992,
Pubmed Cochran,
Molecular cloning of gene sequences regulated by platelet-derived growth factor.
1983,
Pubmed Czuwara-Ladykowska,
Fli-1 inhibits collagen type I production in dermal fibroblasts via an Sp1-dependent pathway.
2001,
Pubmed Deshane,
Sp1 regulates chromatin looping between an intronic enhancer and distal promoter of the human heme oxygenase-1 gene in renal cells.
2010,
Pubmed Dittmer,
The biology of the Ets1 proto-oncogene.
2003,
Pubmed Doyle,
Toll-like receptors: from the discovery of NFkappaB to new insights into transcriptional regulations in innate immunity.
2006,
Pubmed Findlay,
Understanding the role of ETS-mediated gene regulation in complex biological processes.
2013,
Pubmed Georgiou,
Expression of ets family of genes in systemic lupus erythematosus and Sjogren's syndrome.
1996,
Pubmed Gottschalk,
Molecular regulation of the human IL-3 gene: inducible T cell-restricted expression requires intact AP-1 and Elf-1 nuclear protein binding sites.
1993,
Pubmed Gu,
Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1.
2000,
Pubmed Hsu,
Sequence and functional properties of Ets genes in the model organism Drosophila.
2000,
Pubmed Hsu,
Ets proteins in biological control and cancer.
2004,
Pubmed Karim,
The ETS-domain: a new DNA-binding motif that recognizes a purine-rich core DNA sequence.
1990,
Pubmed Li,
Regulation of Ets function by protein - protein interactions.
2000,
Pubmed Low,
Wound healing in MIP-1alpha(-/-) and MCP-1(-/-) mice.
2001,
Pubmed Mantovani,
Monocyte chemotactic protein-1 (MCP-1): signal transduction and involvement in the regulation of macrophage traffic in normal and neoplastic tissues.
1993,
Pubmed Martin,
Characterization of the murine C3a receptor enhancer-promoter: expression control by an activator protein 1 sequence and an Ets-like site.
2005,
Pubmed Mastrangelo,
DNA looping and Sp1 multimer links: a mechanism for transcriptional synergism and enhancement.
1991,
Pubmed Mathenia,
Impact of Fli-1 transcription factor on autoantibody and lupus nephritis in NZM2410 mice.
2010,
Pubmed Mills,
Systemic lupus erythematosus.
1994,
Pubmed Monti,
The CC chemokine MCP-1/CCL2 in pancreatic cancer progression: regulation of expression and potential mechanisms of antimalignant activity.
2003,
Pubmed Morel,
Polygenic control of susceptibility to murine systemic lupus erythematosus.
1994,
Pubmed Negus,
The detection and localization of monocyte chemoattractant protein-1 (MCP-1) in human ovarian cancer.
1995,
Pubmed Perry,
Murine models of systemic lupus erythematosus.
2011,
Pubmed Ping,
Sp1 binding is critical for promoter assembly and activation of the MCP-1 gene by tumor necrosis factor.
2000,
Pubmed Ping,
TNF regulates the in vivo occupancy of both distal and proximal regulatory regions of the MCP-1/JE gene.
1996,
Pubmed Rollins,
Chemokines.
1997,
Pubmed Rollins,
Cloning and expression of JE, a gene inducible by platelet-derived growth factor and whose product has cytokine-like properties.
1988,
Pubmed Sementchenko,
Ets target genes: past, present and future.
2000,
Pubmed Singh,
Lupus nephritis.
2009,
Pubmed Suzuki,
Fli-1 transcription factor affects glomerulonephritis development by regulating expression of monocyte chemoattractant protein-1 in endothelial cells in the kidney.
2012,
Pubmed Svenson,
The mouse and human Fli1 genes are similarly regulated by Ets factors in T cells.
2010,
Pubmed Tesch,
Monocyte chemoattractant protein 1-dependent leukocytic infiltrates are responsible for autoimmune disease in MRL-Fas(lpr) mice.
1999,
Pubmed Theofilopoulos,
Murine models of systemic lupus erythematosus.
1985,
Pubmed Thomas,
ETS1, NFkappaB and AP1 synergistically transactivate the human GM-CSF promoter.
1997,
Pubmed Ueda,
NF-kappa B and Sp1 regulate transcription of the human monocyte chemoattractant protein-1 gene.
1994,
Pubmed Wang,
Activation of the granulocyte-macrophage colony-stimulating factor promoter in T cells requires cooperative binding of Elf-1 and AP-1 transcription factors.
1994,
Pubmed Watson,
The ERGB/Fli-1 gene: isolation and characterization of a new member of the family of human ETS transcription factors.
1992,
Pubmed Zhan,
Ets-1 is a critical regulator of Ang II-mediated vascular inflammation and remodeling.
2005,
Pubmed Zhang,
Generation and characterization of monoclonal antibodies against the ERGB/FLI-1 transcription factor.
1995,
Pubmed Zhang,
Decreased expression of the Ets family transcription factor Fli-1 markedly prolongs survival and significantly reduces renal disease in MRL/lpr mice.
2004,
Pubmed Zhang,
An immunological renal disease in transgenic mice that overexpress Fli-1, a member of the ets family of transcription factor genes.
1995,
Pubmed Zhou,
Regulation of monocyte chemoattractant protein (MCP)-1 transcription by interferon-gamma (IFN-gamma) in human astrocytoma cells: postinduction refractory state of the gene, governed by its upstream elements.
2001,
Pubmed
