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Mara Lennard Richard, Shuzo Sato, Eiji Suzuki, Sarah Williams, Tamara Nowling, Xian Zhang, Identification of Fli-1 as a novel regulator of the inflammatory chemokine CCL5/RANTES (CCR5P.253), The Journal of Immunology, Volume 192, Issue Supplement_1, May 2014, Page 181.7, https://doi.org/10.4049/jimmunol.192.Supp.181.7
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Abstract
The Fli-1 transcription factor is implicated in the pathogenesis of systemic lupus erythematosus (SLE) in both human patients and murine models of lupus. Lupus-prone mice with reduced Fli-1 expression have significantly less nephritis, prolonged survival and significantly decreased infiltrating inflammatory cells into the kidney. The chemokine, CCL5, attracts inflammatory cells and expression is increased in patients with SLE. In this study, decreased expression of CCL5 mRNA was observed in kidneys of NZM2410 mice with reduced Fli-1 expression. CCL5 protein expression was significantly impaired in endothelial cells treated with Fli-1 specific siRNA compared to controls. Fli-1 binds to Ets binding sites in the CCL5 promoter and transfection assays show that Fli-1 drives transcription in a dose-dependent manner. Mutation of the Fli-1 DNA binding domain demonstrates that activation of the CCL5 promoter is through direct binding by Fli-1. Ets1 also drives transcription from the CCL5 promoter, although Fli-1 driven transactivation is significantly stronger. The Ets1 transcription factor acts as a dominant negative to Fli-1, indicating that the genes may share a DNA binding site. Fli-1 is a novel regulator of CCL5 gene transcription. Combined with previous results, demonstrating that Fli-1 regulates MCP-1, we conclude that Fli-1 is a critical regulator of proinflammatory chemokines and affects disease pathogenesis by regulating factors involved inflammatory cell recruitment.
