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Mol Immunol. 2015 Feb;63(2):566-73. doi: 10.1016/j.molimm.2014.07.013. Epub 2014 Aug 6.

Fli-1 controls transcription from the MCP-1 gene promoter, which may provide a novel mechanism for chemokine and cytokine activation.

Author information

1
Department of Medicine, Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
2
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.
3
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.
4
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.

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.

KEYWORDS:

Chemokines; Fli-1; Gene regulation; Inflammation; MCP-1; Transcriptional factors

PMID:
25108845
PMCID:
PMC4254164
DOI:
10.1016/j.molimm.2014.07.013
[Indexed for MEDLINE]
Free PMC Article

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