Notch1 upregulates LPS-induced macrophage activation by increasing NF-κB activity
Notch1 upregulates LPS-induced macrophage activation by increasing NF-κB activity
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DOI：
10.1002/eji.200838722
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发表时间：
2009-09-01
影响因子：
5.4
通讯作者：
Diaz-Guerra, Maria Jose M.
中科院分区：
文献类型：
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作者：
Monsalve, Eva;Ruiz-Garcia, Almudena;Diaz-Guerra, Maria Jose M.
巨噬细胞表面呈现不同的Notch受体和配体。巨噬细胞被内毒素或其他TLR配体激活后，Notch1的表达上调。我们在这里报道，Notch信号增加了基础和内毒素诱导的NF-kappa B的激活，有利于炎症反应中涉及的基因的表达，如细胞因子TNF-α和IL-6，或酶，如iNOS。Delta4似乎是诱导巨噬细胞Notch激活和增加核因子-kappaB转录活性的最有效的配体。我们发现Notch1信号通过增加I-kappa B激酶α/β复合体的磷酸化和一些NF-kappa B家族成员的表达来促进核转录因子-kappa B转位到细胞核和DNA结合。巨噬细胞用伽马分泌酶抑制剂DAPT处理，可阻止Notch受体的切割和激活，从而抑制所有这些过程，降低内毒素刺激后的NF-kappa B活性。此外，我们还发现，细胞内活性的Notch片段可以直接与肿瘤坏死因子-α和诱导型一氧化氮合酶启动子相互作用。我们的结果表明，Notch信号通过增强NF-kappa B信号导致巨噬细胞依赖的炎症反应的放大。
Macrophages present different Notch receptors and ligands on their surface. Following macrophage activation by LPS or other TLR ligands, Notch1 expression is upregulated. We report here that Notch signaling increases both basal and LPS-induced NF-kappa B activation, favoring the expression of genes implicated in the inflammatory response, such as the cytokines TNF-alpha and IL-6, or enzymes, such as iNOS. Delta4 seems to be the most effective ligand to induce Notch activation and increasing NF-kappa B transcriptional activity in macrophages. We show that Notch1 signaling promotes NF-kappa B translocation to the nucleus and DNA binding by increasing both phosphorylation of the I kappa B kinase alpha/beta complex and the expression of some NF-kappa B family members. Treatment of macrophages with the gamma-secretase inhibitor DAPT, which prevents the cleavage and activation of Notch receptors, inhibits all these processes, diminishing NF-kappa B activity following LPS stimulation. Additionally, we show that the active intracellular Notch fragment can directly interact with TNF-alpha and iNOS promoters. Our results suggest that Notch signaling results in an amplification of the macrophage-dependent inflammatory response by enhancing NF-kappa B signaling.