Kasutani K, Itoh N, Kanekiyo M, Muto N, Tanaka K
Faculty of Pharmaceutical Sciences, Osaka University, Yamada-oka, Suita, Osaka, 565-0871, Japan.
Toxicol Appl Pharmacol. 1998 Jul;151(1):143-51. doi: 10.1006/taap.1998.8452.
Metallothionein (MT)-inducing activity of interleukin (IL)-6 depends on the presence of glucocorticoid in hepatic cells. The synergistic action of IL-6 and glucocorticoid was observed in the transcriptional activation of the mouse MT (mMT)-I gene. We found that a 281-bp promoter was sufficient for IL-6 and glucocorticoid stimulation. Our inspection of this region revealed the putative type 1 and 2 IL-6 responsive elements (REs). Functional analyses of these regions were performed using luciferase reporter constructs, and it was observed that the type 2 IL-6RE exerted the major response to the IL-6 signal. The transcriptional factor binding to type 1 IL-6RE, nuclear factor-IL-6, hardly contributed to the activation of the mMT-I promoter by IL-6 and glucocorticoid. A glucocorticoid responsive element (GRE) was also required for the synergistic activation by IL-6 and glucocorticoid. Interestingly, this synergism was not observed when the type 2 IL-6RE and the GRE were kept apart. Therefore, the synergistic activation of the mMT-I gene by IL-6 and glucocorticoid may require not only that signal transducers and activators 3 (Stat3) and the glucocorticoid receptor (GR) bind to their respective responsive elements, but also that Stat3 and the GR physically interact with one another.
白细胞介素（IL）-6诱导金属硫蛋白（MT）的活性取决于肝细胞中糖皮质激素的存在。在小鼠MT（mMT）-I基因的转录激活中观察到IL-6与糖皮质激素的协同作用。我们发现一个281 bp的启动子足以对IL-6和糖皮质激素产生应答。我们对该区域的检查揭示了假定的1型和2型IL-6反应元件（RE）。使用荧光素酶报告构建体对这些区域进行功能分析，观察到2型IL-6RE对IL-6信号发挥主要应答作用。与1型IL-6RE结合的转录因子核因子-IL-6对IL-6和糖皮质激素激活mMT-I启动子几乎没有作用。IL-6与糖皮质激素的协同激活也需要糖皮质激素反应元件（GRE）。有趣的是，当2型IL-6RE与GRE分开时未观察到这种协同作用。因此，IL-6与糖皮质激素对mMT-I基因的协同激活可能不仅需要信号转导子和激活子3（Stat3）以及糖皮质激素受体（GR）与其各自的反应元件结合，还需要Stat3与GR相互之间发生物理相互作用。
