IFN-regulatory factor 5 (IRF-5), a member of the IRF family, is a transcription factor that has a key role in the induction of the antiviral and inflammatory response. When compared with C57BL/6 mice, Irf5 −/− mice show higher susceptibility to viral infection and de- in Toll-like receptor (TLR) 7-and TLR9-induced IL-6 production, and the aged Irf5 −/− mice have decreased serum levels of natural antibodies; however, the antigen-specific IgG1 primary response was already dependent in IRF-5 in young mice, although the IgM response was not. Analysis of the profile of transcription factors associated with plasma cell differentiation shows down-regulation of Blimp-1 expression, a master regulator of plasma cell differentiation, which can be reconstituted with ectopic IRF-5. IRF-5 stimulates transcription of the Prdm1 gene encoding Blimp-1 and binds to the IRF site in the Prdm1 promoter. Collectively, these results reveal that the age-related splenomegaly in Irf5 he roles of IFN-regulatory factor (IRF) 3 and IRF-7 in the antiviral response have been well established, and their function in induction of type I Ifn genes has been extensively characterized (1, 2). The in vitro studies indicated that IRF-5 may also be involved in the antiviral response, but it was only recently that Irf5 −/− mice became available and the importance of IRF-5 in the antiviral and inflammatory response in vivo was clearly demonstrated (3, 4). Irf5 −/− mice exhibit high susceptibility to viral infection and show reductions in serum levels of type I IFN as well as inflammatory cytokines (4). Irf5−/− mice also show resistance to lethal shock induced by unmethylated CpG DNA and LPS (3). IRF-5 expression is induced by type I IFN and viral infection. In humans, IRF-5 is expressed in multiple spliced variants (5), and a distinct polymorphism in the IRF-5 gene is associated with autoimmune diseases such as systemic lupus erythematosus (6) and rheumatoid arthritis (7).The aim of this study was to examine the role of IRF-5 in B-cell development and differentiation, because we had observed that Irf5 −/− mice exhibit age-related splenomegaly associated with a large increase in CD19 + cells. Here, we demonstrate that Irf5 −/− mice show a dramatic increase in CD19 + B220− cells and attenuation of plasma cell development. Addressing the molecular mechanism responsible for this impairment, we show that IRF-5 regulates expression of the plasma cell maturation protein Blimp-1. Blimp-1 encoded by Prdm1 is required for the formation of Ig-secreted plasma cells (8). In mice, B cells specific for Blimp-1 deficiency result in attenuation of plasma cell development and a reduction in the humoral antigenic response (9). Thus, our results reveal the importance of IRF-5 in B-cell development and the commitment to terminal B-cell differentiation by stimulating expression of Blimp-1, the master regulator of plasma cell differentiation.

Core-binding factors are a small family of heterodimeric transcription factors that play critical roles in development. Whereas Cbfa-1, one of the three ␣ subunits in the family, is essential for osteogenesis, Cbfb, the only ␤ subunit, forms heterodimers with different Cbfas to increase their DNA binding affinity by inducing conformational changes. Although defective bone formation was found in both Cbfa-1 and Cbfb knockout animals, the precise role of the latter in osteogenesis remains unclear. To dissect the contribution of Cbfb in osteogenic differentiation of mesenchymal stem cells (MSCs), recombinant adenoviruses carrying Cbfb (AdHACbfb) and Cbfa-1 (AdCbfa-1) were generated and used to infect both the mouse C3H10T1/2 cells and human bone marrow-derived MSCs. Although Cbfb alone failed to trigger osteogenesis of MSCs, it markedly enhanced the gene expression and enzyme activity of alkaline phosphatase as well as osteocalcin activation in those cells overexpressing Cbfa-1. Enhancement of the osteogenic differentiation-inducing effect of Cbfa-1 by Cbfb resulted from an increase in stability of the former due to the suppression of ubiquitination-mediated proteasomal degradation by the latter. Taken together, in addition to defining the role of Cbfb in osteogenic differentiation of MSCs, our results also suggest that the Cbfa-1 and Cbfb coexpressing MSCs might be an appropriate strategy for bone repairing and regeneration therapies.