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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >IRAK1BP1 inhibits inflammation by promoting nuclear translocation of NF-κB p50
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IRAK1BP1 inhibits inflammation by promoting nuclear translocation of NF-κB p50

机译：IRAK1BP1通过促进NF-κBp50的核转运来抑制炎症

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摘要

An orchestrated balance of pro- and antiinf lammatory cytokine release is critical for an innate immune response sufficient for pathogen defense without excessive detriment to host tissues. By using an unbiased forward genetic approach, we previously reported that IL-1R-associated kinase 1 binding protein 1 (IRAK1BP1) down-modulates Toll-like receptor-mediated transcription of several proinflammatory cytokines. To gain insights into the physiological relevance of the inhibitory role of IRAK1BP1 in inflammation, we generated mutant mice lacking IRAK1BP1. Here we report that IRAKI BP1 does not inhibit signaling pathways generally but rather changes the transcriptional profile of activated cells, leading to an increase in IL-10 production and promoting LPS tolerance. This shift in cytokine transcription correlates with an increased ratio of functional NF-kB subunit dimers comprised of p50/p50 homodimers relative to p50/p65 heterodimers. The increase in nuclear p50/p50 was consistent with the ability of IRAK1BP1 to bind to the p50 precursor molecule and IκB family member p105. We conclude that IRAK1BP1 functions through its effects on NF-kB as a molecular switch to bias innate immune pathways toward the resolution of inflammation.
机译：促炎性和抗炎性细胞因子释放的协调平衡对于足以抵抗病原体而又不会损害宿主组织的先天免疫应答至关重要。通过使用无偏正向遗传方法，我们先前曾报道IL-1R相关激酶1结合蛋白1（IRAK1BP1）下调Toll样受体介导的几种促炎细胞因子的转录。为了深入了解IRAK1BP1在炎症中的抑制作用的生理相关性，我们生成了缺少IRAK1BP1的突变小鼠。在这里，我们报告IRAKI BP1一般不会抑制信号通路，而是会改变活化细胞的转录谱，从而导致IL-10产生增加并促进LPS耐受性。细胞因子转录的这种变化与由p50 / p50同二聚体组成的功能性NF-kB亚基二聚体相对于p50 / p65异二聚体的比例增加有关。核p50 / p50的增加与IRAK1BP1与p50前体分子和IκB家族成员p105结合的能力一致。我们得出结论，IRAK1BP1通过其对NF-kB的作用而发挥功能，该分子开关是将先天免疫途径偏向炎症消退的分子开关。

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  • 作者

    James R. Conner; Irina I. Smirnova; Annie Park Moseman; Alexander Poltorak;

  • 作者单位

    Graduate Program in Immunology, Tufts University Sackler School of Biomedical Sciences, Boston, MA 02111 Medical Scientist Training Program, Tufts University Sackler School of Biomedical Sciences, Boston, MA 02111;

    rnDepartment of Pathology, Tufts University School of Medicine, Boston, MA 02111;

    rnGraduate Program in Immunology, Tufts University Sackler School of Biomedical Sciences, Boston, MA 02111;

    rnGraduate Program in Immunology, Tufts University Sackler School of Biomedical Sciences, Boston, MA 02111 Department of Pathology, Tufts University School of Medicine, Boston, MA 02111;

  • 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

    inhibitor; innate immunity; p105; toll-like receptor; tolerance;

    机译：抑制剂先天免疫;p105;收费型受体公差;

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