Late-phase synthesis of IκBα insulates the TLR4-activated canonical NF-κB pathway from noncanonical NF-κB signaling in macrophages.
Late-phase synthesis of IκBα insulates the TLR4-activated canonical NF-κB pathway from noncanonical NF-κB signaling in macrophages.
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巨噬细胞中IκBα的晚期合成使TLR 4激活的经典NF-κB通路与非经典NF-κB信号传导隔离。
DOI：
10.1126/scisignal.aaf1129
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发表时间：
2016-12-06
影响因子：
7.3
通讯作者：
Basak S
中科院分区：
文献类型：
--
作者：
Chatterjee B;Banoth B;Mukherjee T;Taye N;Vijayaragavan B;Chattopadhyay S;Gomes J;Basak S
核因子κB(NF-κB)转录因子在微生物感染过程中协调炎性免疫反应。致病物质通过异源二聚体RelA：P50参与典型的NF-κB信号转导，受到κBα抑制物(IκBα)的快速负反馈。非规范的NF-κB途径是免疫细胞分化所必需的；然而，这两条途径之间可能会发生串扰。伴随激活的非正则信号从P100前体产生P52。P100的合成是由典型信号诱导的，导致形成晚期作用的RelA：P52异源二聚体。这种串扰延长了上皮细胞中的炎性关联活动，以确保病原体清除。我们发现在小鼠巨噬细胞系中，Toll样受体4(TLR4)激活的典型的NF-κB信号通路与淋巴毒素β受体(LTβR)诱导的非典型信号通路是隔离的。结合计算和生化研究表明，Nfkbia的NF-κB反应表达的程度与串扰呈负相关。Nfkbia编码IκBα。与成纤维细胞相比，Nfkbia启动子在巨噬细胞中对NF-κB激活的反应性增强。我们发现，这个高反应性启动子通过TLR4和LTβR与巨噬细胞共刺激过程中产生的RelA：P52二聚体结合，在后期时间点触发IκBα的合成，从而阻止了晚期作用的RELA串扰反应。综上所述，这些数据表明，尽管不同谱系的细胞中存在相同的信号网络，但信号通路之间出现的串扰受到细胞类型特定调控的影响。我们认为，规范和非规范的NF-κB通路的隔离限制了巨噬细胞介导的炎症的有害影响。
The nuclear factor κB (NF-κB) transcription factors coordinate the inflammatory immune response during microbial infection. Pathogenic substances engage canonical NF-κB signaling through the heterodimer RelA:p50, which is subjected to rapid negative feedback by inhibitor of κBα (IκBα). The noncanonical NF-κB pathway is required for the differentiation of immune cells; however, crosstalk between both pathways can occur. Concomitantly activated noncanonical signaling generates p52 from the p100 precursor. The synthesis of p100 is induced by canonical signaling, leading to formation of the late-acting RelA:p52 heterodimer. This crosstalk prolongs inflammatory RelA activity in epithelial cells to ensure pathogen clearance. We found that the Toll-like receptor 4 (TLR4)–activated canonical NF-κB signaling pathway is insulated from lymphotoxin β receptor (LTβR)–induced noncanonical signaling in mouse macrophage cell lines. Combined computational and biochemical studies indicated that the extent of NF-κB–responsive expression of Nfkbia, which encodes IκBα, inversely correlated with crosstalk. The Nfkbia promoter showed enhanced responsiveness to NF-κB activation in macrophages compared to that in fibroblasts. We found that this hyperresponsive promoter engaged the RelA:p52 dimer generated during costimulation of macrophages through TLR4 and LTβR to trigger synthesis of IκBα at late time points, which prevented the late-acting RelA crosstalk response. Together, these data suggest that despite the presence of identical signaling networks in cells of diverse lineages, emergent crosstalk between signaling pathways is subject to cell type–specific regulation. We propose that the insulation of canonical and noncanonical NF-κB pathways limits the deleterious effects of macrophage-mediated inflammation.