Takeda T, Kurachi H, Yamamoto T, Nishio Y, Nakatsuji Y, Morishige K i, Miyake A, Murata Y
Department of Obstetrics and Gynecology, Osaka University Medical School, Osaka 565-0871, Japan.
J Endocrinol. 1998 Nov;159(2):323-30. doi: 10.1677/joe.0.1590323.
Cytokines and steroid hormones use different sets of signal transduction pathways, which seem to be unrelated. Interleukin-6 (IL-6) uses JAK tyrosine kinase and STAT (signal transducer and activator of transcription) transcription factor. Glucocorticoid binds glucocorticoid receptor (GR), which is a member of the steroid receptor superfamily. We have studied the crosstalk between the IL-6-JAK-STAT and glucocorticoid-nuclear receptor pathways. IL-6 and glucocorticoid synergistically activated the IL-6 response element on the rat alpha2-macroglobulin promoter (APRE)-driven luciferase gene. The exogenous expression of GR enhanced the synergism. The exogenous expression of dominant negative STAT3 completely abolished the IL-6 plus glucocorticoid-induced activation of the APRE-luciferase gene. Tyrosine phosphorylation of STAT3 stimulated by IL-6 alone was not different from that by IL-6 plus glucocorticoid. The protein level of STAT3 was also not increased by glucocorticoid stimulation. The time course of STAT3 tyrosine phosphorylation by IL-6 plus glucocorticoid was not different from that by IL-6 alone. The synergism was studied on the two other IL-6 response elements, the junB promoter (JRE-IL-6) and the interferon regulatory factor-1 (IRF-1) promoter (IRF-GAS) which could be activated by STAT3. The synergistic activation by glucocorticoid on the IL-6-activated JRE-IL-6 and the IRF-GAS-driven luciferase gene was not detected. Glucocorticoid did not change the mobility of IL-6-induced APRE-binding proteins in a gel shift assay. These results suggest that the synergism was through the GR and STAT3, and the coactivation pathway which was specific for APRE was the target of glucocorticoid.
细胞因子和类固醇激素使用不同的信号转导途径组，这些途径似乎并无关联。白细胞介素-6（IL-6）使用JAK酪氨酸激酶和STAT（信号转导子和转录激活子）转录因子。糖皮质激素与糖皮质激素受体（GR）结合，GR是类固醇受体超家族的成员。我们研究了IL-6-JAK-STAT和糖皮质激素-核受体途径之间的相互作用。IL-6和糖皮质激素协同激活大鼠α2-巨球蛋白启动子（APRE）驱动的荧光素酶基因上的IL-6反应元件。GR的外源性表达增强了协同作用。显性负性STAT3的外源性表达完全消除了IL-6加糖皮质激素诱导的APRE-荧光素酶基因的激活。单独由IL-6刺激引起的STAT3酪氨酸磷酸化与由IL-6加糖皮质激素引起的并无差异。糖皮质激素刺激也未使STAT3的蛋白水平升高。IL-6加糖皮质激素引起的STAT3酪氨酸磷酸化的时间进程与单独由IL-6引起的并无差异。在另外两个可被STAT3激活的IL-6反应元件，即junB启动子（JRE-IL-6）和干扰素调节因子-1（IRF-1）启动子（IRF-GAS）上研究了协同作用。未检测到糖皮质激素对IL-6激活的JRE-IL-6和IRF-GAS驱动的荧光素酶基因的协同激活作用。在凝胶迁移试验中，糖皮质激素未改变IL-6诱导的APRE结合蛋白的迁移率。这些结果表明，协同作用是通过GR和STAT3实现的，且对APRE具有特异性的共激活途径是糖皮质激素的作用靶点。
