Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, Hospital for Special Surgery, New York, NY 10021, USA.
J Immunol. 2010 Nov 1;185(9):5023-31. doi: 10.4049/jimmunol.1001544. Epub 2010 Sep 24.
Several signaling pathways, including the Notch pathway, can modulate TLR activation to achieve responses most appropriate for the environment. One mechanism of TLR-Notch cross-talk is TLR-induced expression of Notch ligands Jagged and Delta that feed back to engage Notch receptors on TLR-activated cells. In this study, we investigated mechanisms by which TLRs induce Notch ligand expression in primary macrophages. TLRs induced Jagged1 expression rapidly and independently of new protein synthesis. Jagged1 induction was augmented by IFN-γ, was partially dependent on canonical TLR-activated NF-κB and MAPK signaling pathways, and elevated Jagged1 expression augmented TLR-induced IL-6 production. Strikingly, TLR-induced Jagged1 expression was strongly dependent on the Notch master transcriptional regulator RBP-J and also on upstream components of the Notch pathway γ-secretase and Notch1 and Notch2 receptors. Thus, Jagged1 is an RBP-J target gene that is activated in a binary manner by TLR and Notch pathways. Early and direct cooperation between TLR and Notch pathways leads to Jagged1-RBP-J-mediated autoamplification of Notch signaling that can modulate later phases of the TLR response.
几种信号通路，包括 Notch 通路，可以调节 TLR 的激活，以实现最适合环境的反应。TLR-Notch 串扰的一种机制是 TLR 诱导 Notch 配体 Jagged 和 Delta 的表达，这些配体反馈作用于 TLR 激活细胞上的 Notch 受体。在这项研究中，我们研究了 TLR 在原代巨噬细胞中诱导 Notch 配体表达的机制。TLR 迅速诱导 Jagged1 表达，而不依赖于新的蛋白质合成。IFN-γ 增强 Jagged1 的诱导，部分依赖于经典的 TLR 激活的 NF-κB 和 MAPK 信号通路，Jagged1 表达的升高增强了 TLR 诱导的 IL-6 产生。引人注目的是，TLR 诱导的 Jagged1 表达强烈依赖于 Notch 主转录调节因子 RBP-J，以及 Notch 通路的上游组件 γ-分泌酶和 Notch1 和 Notch2 受体。因此，Jagged1 是一种 RBP-J 靶基因，它以二元方式被 TLR 和 Notch 通路激活。TLR 和 Notch 通路之间的早期和直接合作导致 Jagged1-RBP-J 介导的 Notch 信号的自动放大，从而可以调节 TLR 反应的后期阶段。
