5a). Group 4 mice (Fli-1+/− Fli-1+/−) had the lowest renal scores of the four groups of mice with BM transplantation. Compared to group 3 (WT WT) mice, group 2 mice (WT Fli-1+/−) also had reduced renal pathological scores, although the difference is not statistically significant. To assess the impact of reduced expression of Fli-1 in haematopoietic versus non-haematopoietic cell lineages on survival in MRL/lpr mice, an additional four groups of mice were generated and followed without MI-503 concentration manipulation. As shown in Fig. 6, by 51 weeks after BM transplantation, 50·5% of group 1 (Fli-1+/−
WT) mice had survived compared to 24% of group 3 mice (WT WT, P = 0·0194). The survival of group 2 (WT Fli-1+/−) mice was also improved compared to group 3 mice, as 50% of group 3 mice died at the age of 24 weeks after BM transplantation, whereas 100% of group 2 mice survived, although the difference in overall survival was not statistically significant (P = 0·0596). As a control, 11 of 12 mice in group 4 (Fli-1+/− Fli-1+/−) mice survived to 51 weeks after BM transplantation. The Fli-1 transcription factor is implicated in lupus disease development in both animal models of lupus and lupus patients [6,7,13]. In this report, we performed BM transplantation to identify the role of haematopoietic versus
non-haematopoietic cell lineages with reduced Fli-1 expression in Staurosporine mouse autoimmune disease development. We hypothesized that Fli-1 expression in both cell lineages would have a significant impact on disease development, as Fli-1+/− MRL/lpr mice had lower autoantibody levels than WT MRL/lpr mice, but the protection against renal disease and death was much greater than the decrease in autoantibody levels. We found, however,
that WT MRL/lpr mice receiving BM from Fli-1+/− mice had significantly lower serum autoantibodies, lower proteinurea, reduced renal disease and longer survival rate compared to WT MRL/lpr mice receiving BM from WT MRL/lpr mice. Fli-1+/− MRL/lpr mice receiving BM from WT MRL/lpr mice also had reduced disease manifestations compared to WT MRL/lpr mice that received BM from WT MRL/lpr mice, Urocanase although disease in these mice was more severe than the WT MRL/lpr mice that received BM from Fli-1+/1 MRL/lpr mice. These data demonstrate that decreased expression of Fli-1 in BM-derived haematopoietic cells plays a significant role on disease development in MRL/lpr mice, while expression of Fli-1 in non-haematopoeitic cells is of less significance. Pathogenic autoantibodies play an important role in lupus disease development. Serum autoantibodies were significantly lower in WT MRL/lpr mice that received BM from Fli-1+/− MRL/lpr mice compared to WT MRL/lpr mice that received BM from WT MRL/lpr mice. The primary effect of reduced expression of Fli-1 on autoantibody production is probably through its role in B cell activation.