Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021, USA.
Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19438-43. doi: 10.1073/pnas.1007816107. Epub 2010 Oct 25.
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 proinflammatory 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-κB 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 proinflammatory 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.
干扰素-γ通过消除反馈抑制途径来增强巨噬细胞固有免疫反应的一个重要机制是消除反馈抑制途径。因此，干扰素-γ消除了内毒素耐受，这是一种主要的负反馈回路，它沉默了先前暴露于内毒素/Toll 样受体 (TLR) 配体的巨噬细胞中炎症细胞因子基因的表达。干扰素-γ抑制内毒素耐受的机制尚未阐明。在这里，我们表明，IFN-γ 预处理可防止原代人单核细胞耐受，并恢复 TLR4 介导的各种促炎细胞因子的诱导，包括 IL-6 和 TNFα。令人惊讶的是，IFN-γ 并没有改变耐受单核细胞中 TLR4 信号转导的近端缺陷。相反，IFN-γ 阻断了与耐受相关的 IL6 和 TNF 转录、RNA 聚合酶 II 募集以及 NF-κB 和 CCAAT/增强子结合蛋白 β 转录因子与 IL6 和 TNF 启动子结合的下调。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 诱导的染色质重塑来克服内毒素耐受，从而允许促炎基因的表达。这些结果确定了 IFN-γ 促进巨噬细胞激活的机制，并强调了染色质重塑和转录控制在调节耐受和激活的巨噬细胞中炎症细胞因子产生中的重要性。
