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Decreased Expression of the Ets Family Transcription Factor Fli-1 Markedly Prolongs Survival and Significantly Reduces Renal Disease in MRL/lpr Mice¹

Xian K. Zhang^2,*, Sarah Gallant^*, Ivan Molano^*, Omar M. Moussa, Phillip Ruiz, Demetri D. Spyropoulos, Dennis K. Watson and Gary Gilkeson^*

^* Department of Medicine, Division of Rheumatology and Immunology, Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center, and Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425; and University of Miami School of Medicine, Miami, FL 33136

Increased Fli-1 mRNA is present in PBLs from systemic lupus erythematosus patients, and transgenic overexpression of Fli-1 in normal mice leads to a lupus-like disease. We report in this study that MRL/lpr mice, an animal model of systemic lupus erythematosus, have increased splenic expression of Fli-1 protein compared with BALB/c mice. Using mice with targeted gene disruption, we examined the effect of reduced Fli-1 expression on disease development in MRL/lpr mice. Complete knockout of Fli-1 is lethal in utero. Fli-1 protein expression in heterozygous MRL/lpr (Fli-1^+/–) mice was reduced by 50% compared with wild-type MRL/lpr (Fli-1^+/+) mice. Fli-1^+/– MRL/lpr mice had significantly decreased serum levels of total IgG and anti-dsDNA Abs as disease progressed. Fli-1^+/– MRL/lpr mice had significantly increased splenic CD8⁺ and naive T cells compared with Fli-1^+/+ MRL/lpr mice. Both in vivo and in vitro production of MCP-1 were significantly decreased in Fli-1^+/– MRL/lpr mice. The Fli-1^+/– mice had markedly decreased proteinuria and significantly lower pathologic renal scores. At 48 wk of age, survival was significantly increased in the Fli-1^+/– MRL/lpr mice, as 100% of Fli-1^+/– MRL/lpr mice were alive, in contrast to only 27% of Fli-1^+/+ mice. These findings indicate that Fli-1 expression is important in lupus-like disease development, and that modulation of Fli-1 expression profoundly decreases renal disease and improves survival in MRL/lpr mice.

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