Conaway Evan A, de Oliveira Dalila C, McInnis Christine M, Snapper Scott B, Horwitz Bruce H
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115.
Division of Emergency Medicine, Boston Children's Hospital, Boston, MA 02115.
J Immunol. 2017 Apr 1;198(7):2906-2915. doi: 10.4049/jimmunol.1601781. Epub 2017 Feb 17.
IL-10 limits the magnitude of inflammatory gene expression following microbial stimuli and is essential to prevent inflammatory disease; however, the molecular basis for IL-10-mediated inhibition remains elusive. Using a genome-wide approach, we demonstrate that inhibition of transcription is the primary mechanism for IL-10-mediated suppression in LPS-stimulated macrophages and that inhibited genes can be divided into two clusters. Genes in the first cluster are inhibited only if IL-10 is included early in the course of LPS stimulation and is strongly enriched for IFN-inducible genes. Genes in the second cluster can be rapidly suppressed by IL-10 even after transcription is initiated, and this is associated with suppression of LPS-induced enhancer activation. Interestingly, the ability of IL-10 to rapidly suppress active transcription exhibits a delay following LPS stimulation. Thus, a key pathway for IL-10-mediated suppression involves rapid inhibition of enhancer function during the secondary phase of the response to LPS.
白细胞介素-10（IL-10）可限制微生物刺激后炎症基因表达的程度，对于预防炎症性疾病至关重要；然而，IL-10介导的抑制作用的分子基础仍不清楚。我们采用全基因组方法证明，转录抑制是IL-10在脂多糖（LPS）刺激的巨噬细胞中介导抑制作用的主要机制，且被抑制的基因可分为两类。第一类基因只有在LPS刺激过程早期加入IL-10时才会被抑制，并且在干扰素诱导基因中高度富集。第二类基因即使在转录开始后也能被IL-10迅速抑制，这与LPS诱导的增强子激活受到抑制有关。有趣的是，IL-10迅速抑制活性转录的能力在LPS刺激后会出现延迟。因此，IL-10介导的抑制作用的关键途径涉及在对LPS反应的第二阶段迅速抑制增强子功能。
