Regulation of tumor necrosis factor receptor-1 and the IKK-NF-κB pathway by LDL receptor-related protein explains the antiinflammatory activity of this receptor
Regulation of tumor necrosis factor receptor-1 and the IKK-NF-κB pathway by LDL receptor-related protein explains the antiinflammatory activity of this receptor
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DOI：
10.1182/blood-2007-12-127613
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发表时间：
2008-06-01
期刊：
影响因子：
20.3
通讯作者：
Gonias, Steven L.
中科院分区：
文献类型：
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作者：
Gaultier, Alban;Arandjelovic, Sanja;Gonias, Steven L.
低密度脂蛋白受体相关蛋白 (LRP-1) 在内吞作用和细胞信号传导中直接（通过结合信号转接蛋白）或间接（通过调节其他细胞表面受体的水平）发挥作用。由于最近对啮齿动物的研究表明 LRP-1 可以抑制炎症，因此我们进行了基于活性的蛋白质分析实验，以发现参与炎症、受 LRP-1 调节的新型蛋白酶。我们发现，当 LRP-1 缺失时，激活的补体蛋白酶的积累水平会增加。尽管LRP-1作为Clr和Cls的内吞受体起作用，但在LRP-1缺陷的细胞中补体蛋白酶mRNA表达增加，诱导型一氧化氮合酶(iNOS)和白细胞介素6的表达也增加。 LRP-1 通过 I kappa B 激酶-核因子-kappa B (NF-kappa B) 途径抑制基底细胞信号传导的能力解释了炎症介质表达的调节。从小鼠中分离出的缺乏 LRP-1 的巨噬细胞，表明 iNOS、Clr 和单核细胞趋化蛋白 1 (MCP-1) 的表达增加； MCP-1 表达受到 NF-κ B 拮抗作用的抑制。 LRP-1 抑制 NF-kappa B 活性的机制涉及下调细胞表面肿瘤坏死因子受体 1 (TNFR1)。抑制自分泌 TNFR1 启动的细胞信号传导。 TNF-α 中和抗体选择性抑制 LRP-1 缺陷细胞中的 NF-κ B 活性。我们提出，LRP-1 通过 I kappa B 激酶-NF-kappa B 途径调节 TNFR1 依赖性细胞信号传导，从而间接抑制炎症介质的表达。
Low-density lipoprotein receptor-related protein (LRP-1) functions in endocytosis and in cell signaling directly (by binding signaling adaptor proteins) or indirectly (by regulating levels of other cell-surface receptors). Because recent studies in rodents suggest that LRP-1 inhibits inflammation, we conducted activity-based protein profiling experiments to discover novel proteases, involved in inflammation, that are regulated by LRP-1. We found that activated complement proteases accumulate at increased levels when LRP-1 is absent. Although LRP-1 functions as an endocytic receptor for Clr and Cls, complement protease mRNA expression was increased in LRP-1-deficient cells, as was expression of inducible nitric oxide synthase (iNOS) and interleukin-6. Regulation of expression of inflammatory mediators was explained by the ability of LRP-1 to suppress basal cell signaling through the I kappa B kinase-nuclear factor-kappa B (NF-kappa B) pathway. LRP-1-deficient macrophages, isolated from mice, demonstrated increased expression of iNOS, Clr, and monocyte chemoattractant protein-1 (MCP-1); MCP-1 expression was inhibited by NF-kappa B antagonism. The mechanism by which LRP-1 inhibits NF-kappa B activity involves down-regulating cell-surface tumor necrosis factor receptor-1 (TNFR1) and thus. inhibition of autocrine TNFR1-initiated cell signaling. TNF-alpha-neutralizing antibody inhibited NF-kappa B activity selectively in LRP-1-deficient cells. We propose that LRP-1 suppresses expression of inflammatory mediators indirectly, by regulating TNFR1-dependent cell signaling through the I kappa B kinase-NF-kappa B pathway.