Zamamiri-Davis Faith, Lu Ying, Thompson Jerry T, Prabhu K Sandeep, Reddy Padala V, Sordillo Lorraine M, Reddy C Channa
Department of Veterinary Science and Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park 16802, USA.
Free Radic Biol Med. 2002 May 1;32(9):890-7. doi: 10.1016/s0891-5849(02)00775-x.
Selenium (Se) is an essential micronutrient for all mammalian species and is associated with a variety of physiological functions, notably immune system, in the form of selenoproteins. Inadequate Se nutrition has been linked to various diseases, including rheumatoid arthritis, cardiomyopathy, and cancer. Important to this discussion is that cyclooxygenase-2 (COX-2) is over-expressed in all the aforesaid pathologies; however, a casual relationship between Se status and COX-2 expression remains to be established. The present study is based on the hypothesis that oxidant stress, a consequence of Se deficiency, lowers the activation potential of the redox-sensitive transcription factor, NF-kappaB, and that the activated NF-kappaB is required for the altered expression of COX-2. To test this hypothesis, we have investigated the relationship between Se status and COX-2 expression in response to LPS stimulation in RAW 264.7, a macrophage-like cell line. In Se-deficient cells, the Se-dependent glutathione peroxidase activity (Se-GPx), a measure of Se status, was markedly reduced and the overall oxidative stress was significantly higher than Se-supplemented cells. Upon lipopolysaccharide (LPS) stimulation, we found 2-3-folds higher COX-2 protein expression as well as higher PGE2 levels in Se-deficient cells than Se-supplemented cells. In comparison, COX-1 protein expression was not affected by either LPS stimulation or Se status. Following LPS stimulation, the nuclear localization of NF-kappaB was significantly increased in Se-deficient macrophages, thereby leading to increased expression of COX-2. This is the first report demonstrating an inverse relationship between Se status and the expression of COX-2.
硒（Se）是所有哺乳动物物种必需的微量营养素，以硒蛋白的形式与多种生理功能相关，尤其是免疫系统。硒营养不足与多种疾病有关，包括类风湿性关节炎、心肌病和癌症。在本讨论中重要的是，环氧化酶-2（COX-2）在上述所有病理状态下均过度表达；然而，硒状态与COX-2表达之间的因果关系仍有待确定。本研究基于以下假设：硒缺乏导致的氧化应激会降低氧化还原敏感转录因子NF-κB的激活潜力，而激活的NF-κB是COX-2表达改变所必需的。为了验证这一假设，我们研究了巨噬细胞样细胞系RAW 264.7中硒状态与LPS刺激后COX-2表达之间的关系。在缺硒细胞中，作为硒状态指标的硒依赖性谷胱甘肽过氧化物酶活性（Se-GPx）显著降低，整体氧化应激明显高于补充硒的细胞。在脂多糖（LPS）刺激后，我们发现缺硒细胞中COX-2蛋白表达以及PGE2水平比补充硒的细胞高2-3倍。相比之下，COX-1蛋白表达不受LPS刺激或硒状态的影响。LPS刺激后，缺硒巨噬细胞中NF-κB的核定位显著增加，从而导致COX-2表达增加。这是第一份证明硒状态与COX-2表达呈负相关的报告。
