Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, South Korea.
J Toxicol Environ Health A. 2010;73(21-22):1451-64. doi: 10.1080/15287394.2010.511551.
The organic compound nonylphenol (NP) belongs to the family of alkylphenols and is a product of industrial synthesis formed during phenol alkylation. Nonylphenol is considered to be an endocrine disruptor due to weak ability to mimic estrogen and subsequently to disrupt the natural balance of hormones in a given organism. Since the endocrine and immune systems share portions of common signaling pathways, it is conceivable that NP may also affect immune system functions. However, the influence of NP on inflammation and macrophages responsiveness to NP is unclear. Thus, the effects of NP were investigated on cyclooxygenase (COX)-2 expression in cultured macrophages. NP induced COX-2 protein and gene expression in murine macrophage RAW264.7 cells and enhanced COX-2 promoter activity and prostaglandin E(2) production. Transfection of RAW264.7 cells with hCOX-2 or various deletion and mutation promoter constructs revealed that the cyclic AMP response element (CRE) was the predominant mediator responsive to NP-induced effects. Moreover, transfection with pCRE-Luc plasmid followed by immunoblotting demonstrated that NP activated CRE sites and CRE binding protein (CREB) phosphorylation. NP also increased nuclear CREB accumulation and CREB binding to the COX-2 promoter. Phosphatidylinositol 3 (PI3)-kinase, Akt, and the mitogen-activated protein kinases (MAP kinases) p38 and JNK were also significantly activated by NP. Our data demonstrate that NP induces COX-2 expression through the PI3-kinase/Akt/MAP kinases/CRE pathway. These findings provide insight into the signal transduction pathways involved in the inflammatory responses induced by NP in macrophages.
有机化合物壬基酚（NP）属于烷基酚家族，是苯酚烷基化过程中形成的工业合成产物。由于其弱雌激素模拟能力，壬基酚被认为是一种内分泌干扰物，从而破坏了特定生物体中激素的自然平衡。由于内分泌系统和免疫系统共享部分共同的信号通路，因此可以想象 NP 也可能影响免疫系统功能。然而，NP 对炎症和巨噬细胞对 NP 的反应的影响尚不清楚。因此，研究了 NP 对培养的巨噬细胞中环氧化酶（COX）-2 表达的影响。NP 诱导鼠源巨噬细胞 RAW264.7 中的 COX-2 蛋白和基因表达，并增强 COX-2 启动子活性和前列腺素 E（2）的产生。用 hCOX-2 或各种缺失和突变启动子构建体转染 RAW264.7 细胞表明，环磷酸腺苷反应元件（CRE）是对 NP 诱导作用最敏感的主要介质。此外，用 pCRE-Luc 质粒转染，随后进行免疫印迹表明 NP 激活了 CRE 位点和 CRE 结合蛋白（CREB）磷酸化。NP 还增加了核 CREB 积累和 CREB 与 COX-2 启动子的结合。磷酸肌醇 3（PI3）-激酶、Akt 和丝裂原激活蛋白激酶（MAPK）p38 和 JNK 也被 NP 显著激活。我们的数据表明，NP 通过 PI3-激酶/Akt/MAPK/CRE 通路诱导 COX-2 表达。这些发现为 NP 在巨噬细胞中诱导炎症反应涉及的信号转导通路提供了深入了解。
