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Type I interferons and the cytokine TNF cooperatively reprogram the macrophage epigenome to promote inflammatory activation

机译:I型干扰素和细胞因子TNF协同重新编程巨噬细胞外形蛋白酶以促进炎症激活

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摘要

Cross-regulation of Toll-like receptor (TLR) responses by cytokines is essential for effective host defense, avoidance of toxicity and homeostasis, but the underlying mechanisms are not well understood. Our comprehensive epigenomics approach to the analysis of human macrophages showed that the proinflammatory cytokines TNF and type I interferons induced transcriptional cascades that altered chromatin states to broadly reprogram responses induced by TLR4. TNF tolerized genes encoding inflammatory molecules to prevent toxicity while preserving the induction of genes encoding antiviral and metabolic molecules. Type I interferons potentiated the inflammatory function of TNF by priming chromatin to prevent the silencing of target genes of the transcription factor NF-kappa B that encode inflammatory molecules. The priming of chromatin enabled robust transcriptional responses to weak upstream signals. Similar chromatin regulation occurred in human diseases. Our findings reveal that signaling crosstalk between interferons and TNF is integrated at the level of chromatin to reprogram inflammatory responses, and identify previously unknown functions and mechanisms of action of these cytokines.
机译:Cytokines的CORM样受体(TLR)反应的交叉调节对于有效的宿主防御,避免毒性和稳态是必不可少的,但潜在的机制也不太了解。我们对人巨噬细胞分析的综合表观态组合方法表明,促炎细胞因子TNF和I型干扰素诱导转录级联,改变染色质状态以广泛地重新编程诱导的TLR4诱导的反应。编码炎症分子的TNF耐受基因,以防止毒性,同时保留编码抗病毒和代谢分子的基因的诱导。 I型干扰素通过引发染色质调节TNF的炎症函数,以防止转录因子NF-Kappa B的靶基因沉默编码炎症分子。染色质的引发使鲁棒转录响应能够弱到弱上游信号。类似的染色质调节发生在人类疾病中。我们的发现表明,干扰素和TNF之间的信号串扰在染色蛋白的水平上集成在染色体中以重新编程炎症反应,并确定这些细胞因子的先前未知的功能和作用机制。

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  • 来源
    《Nature immunology》 |2017年第10期|共15页
  • 作者单位

    Hosp Special Surg Arthrit &

    Tissue Degenerat Program 535 E 70th St New York NY 10021 USA;

    Hosp Special Surg Arthrit &

    Tissue Degenerat Program 535 E 70th St New York NY 10021 USA;

    Hosp Special Surg Arthrit &

    Tissue Degenerat Program 535 E 70th St New York NY 10021 USA;

    Hosp Special Surg Arthrit &

    Tissue Degenerat Program 535 E 70th St New York NY 10021 USA;

    Dankook Univ Dept Microbiol Cheonan Chungnam South Korea;

    Hosp Special Surg Arthrit &

    Tissue Degenerat Program 535 E 70th St New York NY 10021 USA;

    Hosp Special Surg Arthrit &

    Tissue Degenerat Program 535 E 70th St New York NY 10021 USA;

    Hosp Special Surg Arthrit &

    Tissue Degenerat Program 535 E 70th St New York NY 10021 USA;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 医学免疫学;
  • 关键词

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