Decreased expression of the Ets family transcription factor Fli-1 markedly prolongs survival and significantly reduces renal disease in MRL/lpr mice

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

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6481-6489
Number of pages9
JournalJournal of Immunology
Volume173
Issue number10
DOIs
StatePublished - Nov 15 2004

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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