Nomura Y
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Life Sci. 2001 Mar 2;68(15):1695-701. doi: 10.1016/s0024-3205(01)00967-5.
This review will discuss the recent literature on the molecular mechanism of NF-kappaB activation, with special focus on IkappaB alpha dynamism involved in iNOS- and chemokine-induction in glial cells. NF-kappaB, a heterotrimer composed of p50, p65 (Rel A) and IkappaB alpha, has been shown to be activated by elimination of the regulatory subunit IkappaB alpha from the heterotrimer. The elimination of IkappaB alpha (formation of active NF-kappaB, p50-p65) is due to phosplorylation of serines 32 and 36 of IkappaB alpha, followed by polyubiquitination and 26S proteasomal degradation of IkappaB alpha. Experiments using stable clones of rat C6 glioma cells transfected with dominant negative IkappaB alpha (serines 32 and 36 replaced by alanine) suggest that NF-kappaB activation (phosphorylation of IkappaB alpha) is involved in LPS/IFNgamma- or IL-1beta/IFNgamma-induced iNOS expression. Furthermore, the time courses of phosphorylation, ubiquitination of IkappaB alpha and proteasome activity after IL-1beta treatment also suggest that 26S proteasomal degradation of IkappaB alpha is more crucial for chemokine expression in glial cells.
本综述将讨论近期有关NF-κB激活分子机制的文献，特别关注参与神经胶质细胞中诱导型一氧化氮合酶（iNOS）和趋化因子诱导的IκBα动态变化。NF-κB是一种由p50、p65（Rel A）和IκBα组成的异源三聚体，已表明可通过从异源三聚体中去除调节亚基IκBα而被激活。IκBα的去除（形成活性NF-κB，p50-p65）是由于IκBα的丝氨酸32和36磷酸化，随后是IκBα的多聚泛素化和26S蛋白酶体降解。使用转染了显性负性IκBα（丝氨酸32和36被丙氨酸取代）的大鼠C6胶质瘤细胞稳定克隆进行的实验表明，NF-κB激活（IκBα磷酸化）参与脂多糖/γ干扰素（LPS/IFNγ）或白细胞介素-1β/γ干扰素（IL-1β/IFNγ）诱导的iNOS表达。此外，白细胞介素-1β处理后IκBα磷酸化、泛素化和蛋白酶体活性的时间进程也表明，IκBα的26S蛋白酶体降解对神经胶质细胞中趋化因子的表达更为关键。
