特种外科医院Lionel B. Ivashkiv研究组报道了IL-10靶向IRF转录因子通过表观遗传机制抑制IFN和炎症反应基因。这一研究成果于2025年4月22日发表在国际顶尖学术期刊《自然—免疫学》上。

在这里，小组利用综合表观基因组分析来研究IL-10介导的LPS和TNF在原代人单核细胞中的抑制作用。与抑制核心TLR4激活通路如NF-κB、MAPK-AP-1和TBK1-IRF3信号传导不同，IL-10靶向IRF转录因子活性和DNA结合，特别是IRF5和IRF1介导的扩增环。这导致炎性NF-κB靶基因的抑制和干扰素刺激基因的几乎完全抑制。基因抑制的机制包括染色质可及性下调、新生增强子形成和IRF1相关的H3K27ac激活组蛋白标记。这些结果提供了IL-10抑制炎症NF-κB靶基因的机制，突出了IRF1在炎症基因表达中的作用，并通过表观遗传机制描述了IFN反应的抑制。

据了解，白细胞介素-10 （IL-10）在抑制先天免疫激活中起关键作用，在很大程度上是通过抑制炎症基因的诱导。尽管经过数十年的研究，这种抑制作用的分子机制尚未得到解决。

附：英文原文

Title: IL-10 targets IRF transcription factors to suppress IFN and inflammatory response genes by epigenetic mechanisms

Author: Mishra, Bikash, Bachu, Mahesh, Yuan, Ruoxi, Wingert, Claire, Chaudhary, Vidyanath, Brauner, Caroline, Bell, Richard, Ivashkiv, Lionel B.

Issue&Volume: 2025-04-22

Abstract: Interleukin-10 (IL-10) is pivotal in suppressing innate immune activation, in large part by suppressing induction of inflammatory genes. Despite decades of research, the molecular mechanisms underlying this inhibition have not been resolved. Here we utilized an integrated epigenomic analysis to investigate IL-10-mediated suppression of LPS and TNF responses in primary human monocytes. Instead of inhibiting core TLR4-activated pathways such as NF-κB, MAPK–AP-1 and TBK1–IRF3 signaling, IL-10 targeted IRF transcription factor activity and DNA binding, particularly IRF5 and an IRF1-mediated amplification loop. This resulted in suppression of inflammatory NF-κB target genes and near-complete suppression of interferon-stimulated genes. Mechanisms of gene inhibition included downregulation of chromatin accessibility, de novo enhancer formation and IRF1-associated H3K27ac activating histone marks. These results provide a mechanism by which IL-10 suppresses inflammatory NF-κB target genes, highlight the role of IRF1 in inflammatory gene expression and describe the suppression of IFN responses by epigenetic mechanisms.

DOI: 10.1038/s41590-025-02137-3

Source: https://www.nature.com/articles/s41590-025-02137-3