NF-κB regulates phagocytic NADPH oxidase by inducing the expression of gp91phox
NF-κB regulates phagocytic NADPH oxidase by inducing the expression of gp91phox
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DOI：
10.1074/jbc.m506172200
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发表时间：
2006-03-03
影响因子：
4.8
通讯作者：
Iadecola, C
中科院分区：
文献类型：
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作者：
Anrather, J;Racchumi, G;Iadecola, C
产生超氧化物的吞噬细胞NADPH氧化酶是针对微生物剂的先天免疫应答的重要组分，并且参与塑造对各种生理和病理信号的细胞应答。NADPH氧化酶衍生的自由基的下游靶标之一是普遍存在的转录因子NF-κ B，其控制参与免疫功能和细胞存活的大量基因的表达。在这里，我们表明，NF-κ B B本身是一个关键因素，控制NADPH氧化酶的表达和功能。在单核细胞和小胶质细胞系中，NADPH氧化酶亚基gp 91（phox）的表达被脂多糖/干扰素γ处理诱导，并在组成型表达I κ B α的细胞中被抑制。此外，在I κ B α过表达的细胞中，可诱导的活性氧的产生被抑制。gp 91（phox）在RelA（-/-）成纤维细胞中的表达非常低，并且可以通过用p65/RelA重建这些细胞来诱导。因此，gp 91（phox）表达依赖于p65/RelA的存在。我们还发现，gp 91（phox）转录依赖于NF-κ B B，我们确定了两个潜在的顺式作用元件在鼠gp 91（phox）启动子，控制NF-κ B依赖性调节。研究结果提出了一个正反馈循环的可能性，其中NF-κ B通过氧化应激激活导致通过NADPH氧化酶进一步产生自由基。
The superoxide-generating phagocytic NADPH oxidase is an important component of the innate immune response against microbial agents, and is involved in shaping the cellular response to a variety of physiological and pathological signals. One of the downstream targets of NADPH oxidase-derived radicals is the ubiquitous transcription factor NF-kappa B, which controls the expression of a large array of genes involved in immune function and cell survival. Here we show that NF-kappa B itself is a key factor in controlling NADPH oxidase expression and function. In monocytic and microglial cell lines, the expression of the NADPH oxidase subunit gp91(phox) was induced by lipopolysaccharide/interferon gamma treatment and was inhibited in cells constitutively expressing I kappa B alpha. Furthermore, inducible reactive oxygen species production was inhibited in I kappa B alpha overexpressing cells. gp91(phox) expression was very low in RelA(-/-) fibroblasts and could be induced by reconstituting these cells with p65/RelA. Thus, gp91(phox) expression is dependent on the presence of p65/RelA. We also found that gp91(phox) transcription is dependent on NF-kappa B and we identified two potential cis-acting elements in the murine gp91(phox) promoter that control NF-kappa B-dependent regulation. The findings raise the possibility of a positive feedback loop in which NF-kappa B activation by oxidative stress leads to further radical production via NADPH oxidase.