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.

The ETS family is a diverse group of transcription factors that control the expressions of genes that participate in an array of cellular activities, ranging from mitosis to apoptosis. As a consequence of regulating these processes, most ETS factors are oncogenic. However, there is growing evidence that ETS factors are also essential to regulation of the immune system. Of the 29 recognized ETS factors, nine are known to regulate genes involved in immunity, including Ets1, Ets2, GABP, Fli1, Elf1, MEF, ESE1, PU.1, and SpiB. These ETS factors typically activate the transcription of genes associated with pathogen and tumor defense, but several also demonstrate ability to repress transcription. Ets1 and PU.1 appear to have the greatest impact on immunity, primarily through their control of immune cell development. Alterations of Fli1 and Elf1 expression are associated with autoimmunity, emphasizing the role of ETS factors as not only positive, but also negative regulators of immunity. This review summarizes the roles of ETS factors in development of the immune system, defense against pathogens and malignancies, and self-tolerance.