NF-κB Links CO2 Sensing to Innate Immunity and Inflammation in Mammalian Cells
NF-κB Links CO2 Sensing to Innate Immunity and Inflammation in Mammalian Cells
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DOI：
10.4049/jimmunol.1000701
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发表时间：
2010-10-01
影响因子：
4.4
通讯作者：
Taylor, Cormac T.
中科院分区：
文献类型：
--
作者：
Cummins, Eoin P.;Oliver, Kathryn M.;Taylor, Cormac T.
分子O-2和CO2分别是有氧代谢的主要底物和产物。这些生理气体在细胞微环境中的水平在健康和疾病中都有很大变化，如慢性炎症、局部缺血和癌症，其中代谢发生了显着改变。缺氧诱导因子的发现，使我们发现了组织中O-2和基因转录之间古老而直接的联系。在这项研究中，我们证明，哺乳动物细胞（小鼠胚胎成纤维细胞和其他）也感觉到局部CO2水平的变化，导致通过NF-κ B B途径改变基因表达。IKK α是NF-κ B B的一种中心调节成分，在CO2浓度升高时迅速可逆地转移至细胞核。这种反应是独立的缺氧诱导因子羟化酶，细胞外和细胞内的pH值，以及介导急性CO2感应线虫和苍蝇，并导致细菌LPS诱导的基因表达衰减的途径。这些结果表明，在哺乳动物细胞中存在分子CO2传感器，其与参与先天免疫和炎症的基因的调节有关。免疫学杂志，2010，185：4439-4445。
Molecular O-2 and CO2 are the primary substrate and product of aerobic metabolism, respectively. Levels of these physiologic gases in the cell microenvironment vary dramatically both in health and in diseases, such as chronic inflammation, ischemia, and cancer, in which metabolism is significantly altered. The identification of the hypoxia-inducible factor led to the discovery of an ancient and direct link between tissue O-2 and gene transcription. In this study, we demonstrate that mammalian cells (mouse embryonic fibroblasts and others) also sense changes in local CO2 levels, leading to altered gene expression via the NF-kappa B pathway. IKK alpha, a central regulatory component of NF-kappa B, rapidly and reversibly translocates to the nucleus in response to elevated CO2. This response is independent of hypoxia-inducible factor hydroxylases, extracellular and intracellular pH, and pathways that mediate acute CO2-sensing in nematodes and flies and leads to attenuation of bacterial LPS-induced gene expression. These results suggest the existence of a molecular CO2 sensor in mammalian cells that is linked to the regulation of genes involved in innate immunity and inflammation. The Journal of Immunology, 2010, 185: 4439-4445.