Departments of Biology and Comparative Medicine, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD 21218, USA.
Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4664-8. doi: 10.1073/pnas.0911193107. Epub 2010 Feb 22.
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 decreased serum levels of type I IFN and the inflammatory cytokines IL-6 and TNF-alpha. Here, we demonstrate that IRF-5 is involved in B-cell maturation and the stimulation of Blimp-1 expression. The Irf5(-/-) mice develop an age-related splenomegaly, associated with a dramatic accumulation of CD19(+)B220(-) B cells and a disruption of normal splenic architecture. Splenic B cells from Irf5(-/-) mice also exhibited a decreased level of plasma cells. The CD19(+) Irf5(-/-) B cells show a defect 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(-/-) mice is associated with an accumulation of CD19(+)B220(-) B cells with impaired functions and show the role of IRF-5 in the direct regulation of the plasma cell commitment factor Blimp-1 and in B-cell terminal differentiation.
干扰素调节因子 5（IRF-5）是 IRF 家族的成员，是一种转录因子，在诱导抗病毒和炎症反应中起着关键作用。与 C57BL/6 小鼠相比，Irf5（-/-）小鼠对病毒感染的敏感性更高，血清 I 型干扰素和炎症细胞因子 IL-6 和 TNF-α水平降低。在这里，我们证明 IRF-5 参与 B 细胞成熟和 Blimp-1 表达的刺激。Irf5（-/-）小鼠出现年龄相关的脾肿大，伴有 CD19（+）B220（-）B 细胞的急剧积累和正常脾脏结构的破坏。Irf5（-/-）小鼠的脾 B 细胞也表现出浆细胞水平降低。CD19（+）Irf5（-/-）B 细胞在 TLR7 和 TLR9 诱导的 IL-6 产生中表现出缺陷，并且衰老的 Irf5（-/-）小鼠血清中天然抗体水平降低；然而，抗原特异性 IgG1 初次反应已经依赖于年轻小鼠中的 IRF-5，尽管 IgM 反应没有。与浆细胞分化相关的转录因子谱分析显示，Blimp-1 表达下调，Blimp-1 是浆细胞分化的主要调节因子，可通过异位 IRF-5 重建。IRF-5 刺激编码 Blimp-1 的 Prdm1 基因的转录，并与 Prdm1 启动子中的 IRF 位点结合。总之，这些结果表明 Irf5（-/-）小鼠的年龄相关脾肿大与功能受损的 CD19（+）B220（-）B 细胞的积累有关，并显示了 IRF-5 在直接调节浆细胞承诺因子 Blimp-1 和 B 细胞终末分化中的作用。
