Fli-1 drives transcription from the MCP-1 gene promoter, which may provide a novel mechanism for cytokine and chemokine activation. (P6236)

Abstract

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). We have demonstrated that Fli-1 binds to three EBSs within the endogenous MCP-1 promoter by ChIP assay. Transient transfection assays of the murine MCP-1 promoter indicate that the Fli-1 gene actively drives transcription from the MCP-1 gene promoter in a dose-dependent manner. The Ets-1 transcription factor was also tested, but failed to drive transcription. Studies to determine the relationship between Fli-1 and Ets-1 in the transcriptional control of MCP-1 will be presented. Deletion studies to determine the most important regions of the MCP-1 promoter for Fli-1 gene regulation are being investigated. Together, these results demonstrate a novel pathway, separate from NFκB, for the transcriptional activation of MCP-1. Evidence suggests that Fli-1 may interact with the promoters of other chemokines and cytokines, providing a novel mechanism for activation of the inflammatory response.