Nam Hae Yun, Choi Byung Hyune, Lee Joo Yong, Lee Seok Geon, Kim Young Hoon, Lee Kweon Haeng, Yoon Hyoung Kyu, Song Jeong Sup, Kim Hyung Jung, Lim Young
Department of Occupational and Environmental Medicine, St. Mary's Hospital, The Catholic University of Korea, Seoul 150-713, South Korea.
Toxicol Lett. 2004 Mar 14;148(1-2):95-102. doi: 10.1016/j.toxlet.2003.12.007.
NFkappaB is one of key transcription factors that are involved in the inflammatory responses to the particulate matter (PM) in the lungs. In order to further understand the molecular mechanism, the effects of antioxidants and an inducible nitric oxide synthase (iNOS) inhibitor on PM-induced NFkappaB activation were examined in A549 lung epithelial cells. NFkappaB activation by 2.5 microm particulates (PM2.5) was evident from the degradation of an NFkappaB inhibitory protein, IkappaBalpha, and a luciferase reporter assay for NFkappaB activity. In these experiments, a pre-treatment of the cells with antioxidants N-acetyl-l-cysteine (NAC) and dimethylthiourea (DMTU) or an iNOS inhibitor l-N6-1-iminoethyl-lysine (L-NIL) clearly inhibited the NFkappaB activation by PM2.5. The inhibitory effect of L-NIL was also observed on the PM2.5-induced interleukin-8 (IL-8) gene expression both at the transcriptional and protein levels. These results suggest that PM2.5 induces NFkappaB activity via the pathways involving ROS and/or RNS generation. Considering the fact that NFkappaB also induces NO generation via iNOS expression, they might make a positive feedback loop that amplifies the downstream responses.
核因子κB（NFκB）是参与肺部对颗粒物（PM）炎症反应的关键转录因子之一。为了进一步了解其分子机制，在A549肺上皮细胞中检测了抗氧化剂和诱导型一氧化氮合酶（iNOS）抑制剂对PM诱导的NFκB激活的影响。通过NFκB抑制蛋白IκBα的降解和NFκB活性的荧光素酶报告基因检测，明显可见2.5微米颗粒物（PM2.5）激活了NFκB。在这些实验中，用抗氧化剂N-乙酰-L-半胱氨酸（NAC）和二甲基硫脲（DMTU）或iNOS抑制剂L-N6-1-亚氨基乙基-赖氨酸（L-NIL）对细胞进行预处理，可明显抑制PM2.5诱导的NFκB激活。在转录和蛋白水平上，还观察到L-NIL对PM2.5诱导的白细胞介素-8（IL-8）基因表达具有抑制作用。这些结果表明，PM2.5通过涉及活性氧（ROS）和/或活性氮（RNS）生成的途径诱导NFκB活性。考虑到NFκB也通过iNOS表达诱导NO生成，它们可能形成一个正反馈环，放大下游反应。
