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-κB 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.

中文翻译：

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I型干扰素和细胞因子TNF协同重编程巨噬细胞表观基因组，以促进炎症激活。

细胞因子对Toll样受体（TLR）应答的交叉调节对于有效的宿主防御，避免毒性和体内稳态至关重要，但其潜在机制尚不清楚。我们对人类巨噬细胞进行分析的综合表观基因组学方法表明，促炎细胞因子TNF和I型干扰素诱导了转录级联反应，从而改变了染色质状态，从而广泛地重编程了由TLR4诱导的反应。TNF耐受的编码炎症分子的基因可防止毒性，同时保留对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来防止编码炎症分子的转录因子NF-κB的靶基因沉默，从而增强TNF的炎症功能。染色质的启动使对弱上游信号的鲁棒转录反应得以实现。在人类疾病中也发生了类似的染色质调节。我们的发现表明，干扰素与TNF之间的信号串扰在染色质水平上得以整合，以重新编程炎症反应，并确定这些细胞因子的先前未知功能和作用机制。