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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >IFN-γ abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling
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IFN-γ abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling

机译：IFN-γ通过促进Toll样受体诱导的染色质重塑来消除内毒素耐受性

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摘要

An important mechanism by which IFN-γ primes macrophages for enhanced innate immune responses is abrogation of feedback inhibitory pathways. Accordingly, IFN-γ abrogates endotoxin tolerance, a major negative feedback loop that silences expression of inflammatory cytokine genes in macrophages previously exposed to endotoxin/Toll-like receptor (TLR) ligands. Mechanisms by which IFN-γ inhibits endotoxin tolerance have not been elucidated. Here, we show that pretreatment with IFN-γ prevented tolerization of primary human monocytes and restored TLR4-mediated induction of various proinf lammatory cytokines, including IL-6 and TNFα. Surprisingly, IFN-γ did not alter proximal TLR4 signaling defects in tolerized monocytes. Instead, IFN-γ blocked tolerance-associated down-regulation of IL6 and TNF transcription, RNA polymerase II recruitment, and NF-kB and CCAAT/enhancer-binding protein β transcription factor binding to the IL6 and TNF promoters in tolerized monocytes. The mechanism by which IFN-γ restored IL6 expression was by facilitating TLR4-induced recruitment of chromatin remodeling machinery to the IL6 promoter and promoting IL6 locus accessibility in tolerized monocytes. Our results suggest that IFN-γ overcomes endotoxin tolerance by facilitating TLR-induced chromatin remodeling to allow expression of proinf lammatory genes. These results identify a mechanism by which IFN-γ promotes activation of macrophages and highlight the importance of chromatin remodeling and transcriptional control in the regulation of inflammatory cytokine production in tolerant and activated macrophages.
机译：IFN-γ引发巨噬细胞增强先天免疫应答的重要机制是废除反馈抑制途径。因此，IFN-γ消除了内毒素耐受性，内毒素耐受性是一个主要的负反馈回路，该回路使先前暴露于内毒素/ Toll样受体（TLR）配体的巨噬细胞中的炎性细胞因子基因表达沉默。还没有阐明IFN-γ抑制内毒素耐受性的机制。在这里，我们表明用IFN-γ进行的预处理可以防止原代人单核细胞的耐受性，并恢复了TLR4介导的各种促炎性细胞因子，包括IL-6和TNFα的诱导。令人惊讶地，IFN-γ没有改变耐受的单核细胞中的近端TLR4信号传导缺陷。相反，IFN-γ阻断了与耐受性相关的IL6和TNF转录下调，RNA聚合酶II募集以及NF-kB和CCAAT /增强子结合蛋白β转录因子与耐受的单核细胞中IL6和TNF启动子的结合。 IFN-γ恢复IL6表达的机制是通过促进TLR4诱导的染色质重塑机制募集到IL6启动子并促进耐受单核细胞中IL6基因座的可及性。我们的结果表明，IFN-γ通过促进TLR诱导的染色质重塑以表达前炎症基因而克服了内毒素耐受性。这些结果确定了IFN-γ促进巨噬细胞活化的机制，并突出了染色质重塑和转录控制在耐受性和活化巨噬细胞中炎性细胞因子产生的调节中的重要性。

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  • 作者

    Janice Chen; Lionel B. lvashkiv;

  • 作者单位

    Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021;

    Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021,Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021;

  • 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

    inflammation; innate immunity; macrophage;

    机译：炎;先天免疫;巨噬细胞;

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