Increased Fli-1 mRNA is present in FBLs 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.
ASJC Scopus subject areas
- Immunology and Allergy