Cummins Eoin P, Oliver Kathryn M, Lenihan Colin R, Fitzpatrick Susan F, Bruning Ulrike, Scholz Carsten C, Slattery Craig, Leonard Martin O, McLoughlin Paul, Taylor Cormac T
UCD Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland.
J Immunol. 2010 Oct 1;185(7):4439-45. doi: 10.4049/jimmunol.1000701. Epub 2010 Sep 3.
Molecular O(2) and CO(2) 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 CO(2) levels, leading to altered gene expression via the NF-κB pathway. IKKα, a central regulatory component of NF-κB, rapidly and reversibly translocates to the nucleus in response to elevated CO(2). This response is independent of hypoxia-inducible factor hydroxylases, extracellular and intracellular pH, and pathways that mediate acute CO(2)-sensing in nematodes and flies and leads to attenuation of bacterial LPS-induced gene expression. These results suggest the existence of a molecular CO(2) sensor in mammalian cells that is linked to the regulation of genes involved in innate immunity and inflammation.
分子氧（O₂）和二氧化碳（CO₂）分别是有氧代谢的主要底物和产物。在健康状态以及诸如慢性炎症、缺血和癌症等疾病状态下，细胞微环境中这些生理气体的水平会发生显著变化，在这些疾病中新陈代谢会发生明显改变。缺氧诱导因子的发现揭示了组织氧与基因转录之间古老而直接的联系。在本研究中，我们证明哺乳动物细胞（小鼠胚胎成纤维细胞及其他细胞）也能感知局部二氧化碳水平的变化，进而通过核因子κB（NF-κB）途径导致基因表达改变。IKKα是NF-κB的核心调控成分，它会响应二氧化碳水平升高而迅速且可逆地转位至细胞核。这种反应独立于缺氧诱导因子羟化酶、细胞外和细胞内pH值，以及线虫和果蝇中介导急性二氧化碳感知的途径，并导致细菌脂多糖诱导的基因表达减弱。这些结果表明哺乳动物细胞中存在一种分子二氧化碳传感器，它与先天免疫和炎症相关基因的调控有关。
