Hayakawa Makio, Miyashita Hiroshi, Sakamoto Isao, Kitagawa Masatoshi, Tanaka Hirofumi, Yasuda Hideyo, Karin Michael, Kikugawa Kiyomi
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Tokyo 192-0392, Japan.
EMBO J. 2003 Jul 1;22(13):3356-66. doi: 10.1093/emboj/cdg332.
It has been postulated that reactive oxygen species (ROS) may act as second messengers leading to nuclear factor (NF)-kappaB activation. This hypothesis is mainly based on the findings that N-acetyl-L-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC), compounds recognized as potential antioxidants, can inhibit NF-kappaB activation in a wide variety of cell types. Here we reveal that both NAC and PDTC inhibit NF-kappaB activation independently of antioxidative function. NAC selectively blocks tumor necrosis factor (TNF)-induced signaling by lowering the affinity of receptor to TNF. PDTC inhibits the IkappaB-ubiquitin ligase activity in the cell-free system where extracellular stimuli-regulated ROS production does not occur. Furthermore, we present evidence that endogenous ROS produced through Rac/NADPH oxidase do not mediate NF-kappaB signaling, but instead lower the magnitude of its activation.
据推测，活性氧（ROS）可能作为第二信使导致核因子（NF）-κB活化。该假说主要基于以下发现：N-乙酰-L-半胱氨酸（NAC）和吡咯烷二硫代氨基甲酸盐（PDTC）这两种被认为是潜在抗氧化剂的化合物，能够在多种细胞类型中抑制NF-κB活化。在此我们揭示，NAC和PDTC均独立于抗氧化功能抑制NF-κB活化。NAC通过降低受体对肿瘤坏死因子（TNF）的亲和力来选择性阻断TNF诱导的信号传导。PDTC在不发生细胞外刺激调节的ROS产生的无细胞系统中抑制IκB泛素连接酶活性。此外，我们提供证据表明，通过Rac/烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶产生的内源性ROS并不介导NF-κB信号传导，而是降低其活化程度。
