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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Critical role of IRF-5 in regulation of B-cell differentiation
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Critical role of IRF-5 in regulation of B-cell differentiation

机译:IRF-5在调节B细胞分化中的关键作用

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摘要

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-α. 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~+ lrfs~(-/-) 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 lgG1 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.
机译:IFN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,并且血清I型IFN和炎性细胞因子IL-6和TNF-α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〜(-/-)小鼠发展出与年龄相关的脾肿大,与CD19〜+ B220〜-B细胞的大量积累和正常脾脏结构的破坏有关。 Irf5〜(-/-)小鼠的脾B细胞也表现出浆细胞水平降低。 CD19〜+ lrfs〜(-/-)B细胞在Toll样受体(TLR)7-和TLR9诱导的IL-6产生缺陷,并且老年Irf5〜(-/-)小鼠血清水平降低天然抗体;然而,尽管IgM反应并非如此,但幼鼠中的抗原特异性IgG1主要反应已经依赖于IRF-5。分析与浆细胞分化有关的转录因子的概况,显示出Blimp-1表达的下调,Blimp-1表达是浆细胞分化的主要调节剂,可以用异位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。总体而言,这些结果表明,Irf5〜(-/-)小鼠中与年龄相关的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IRF-5中的作用。浆细胞定型因子Blimp-1与B细胞终末分化有关。

著录项

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  • 作者单位

    The Sidney Kimmel Comprehensive Cancer Center and Departments of The Johns Hopkins University, Baltimore, MD, 21218;

    Biology and The Johns Hopkins University, Baltimore, MD, 21218;

    Comparative Medicine, The Johns Hopkins University, Baltimore, MD, 21218;

    Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201;

    Department of Genetics, Cell Biology and Anatomy, Nebraska Medical Center, Omaha, NE 68198;

    The Sidney Kimmel Comprehensive Cancer Center and Departments of The Johns Hopkins University, Baltimore, MD, 21218 Biology and The Johns Hopkins University, Baltimore, MD, 21218;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    IRF-5; antigenic response; B-cell development; Blimp-1; toll-like receptors;

    机译:IRF-5;抗原反应B细胞发育;飞艇1;收费样受体;

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