Cell type-specific differential induction of the human gamma-fibrinogen promoter by interleukin-6.
Cell type-specific differential induction of the human gamma-fibrinogen promoter by interleukin-6.
复制标题
DOI：
--
复制
发表时间：
2006
期刊：
影响因子：
--
通讯作者：
H. Duan;P. Simpson-Haidaris
中科院分区：
文献类型：
--
作者：
H. Duan;P. Simpson-Haidaris
在急性期反应期间，白细胞介素-6（IL-6）和糖皮质激素上调肝和肺上皮中三种纤维蛋白原（FBG）基因（fga、fgb和fgg）的表达;然而，很少发生组成性肺表达。最近，我们发现Stat 3与人γ FBG启动子上的三个IL-6基序结合的程度与它们在肝细胞中的功能活性呈负相关，尽管这些顺式元件对启动子活性至关重要。我们确定了IL-6受体-gp 130-Stat 3信号在肝和肺上皮细胞中γ FBG启动子的IL-6激活中的作用。虽然IL-6在HepG 2细胞中诱导γ FBG启动子活性约30倍，但在肺A549细胞中仅增加2倍。通过蛋白质印迹法证明了两种细胞类型中gp 130的等效产生;然而，IL-6受体和Stat 3的较低产生部分地解释了肺细胞中γ FBG启动子的活性降低。地塞米松在HepG 2和A549细胞中增强了IL-6对γ FBG启动子的2.3倍诱导，分别使启动子活性增加70倍或4.5倍。地塞米松增强作用可能是由于诱导IL-6受体表达以及Stat 3激活的强度和持续时间延长。通过用粒细胞集落刺激因子受体（GCSFR）-gp 130（133）嵌合受体的异位表达来规避IL-6-受体-gp 130-偶联的信号传导，Stat 3的过表达在A549细胞中诱导gammaFBG启动子活性30倍。总之，这些数据表明IL-6受体-gp 130偶联信号传导的组织特异性差异，从而限制了肺部炎症期间Stat 3激活和γ FBG表达的程度。
During an acute phase response, interleukin-6 (IL-6) and glucocorticoids up-regulate expression of the three fibrinogen (FBG) genes (fga, fgb, and fgg) in liver and lung epithelium; however, little constitutive lung expression occurs. Recently, we showed that the magnitude of Stat3 binding to three IL-6 motifs on the human gammaFBG promoter correlates negatively with their functional activity in hepatocytes, although these cis-elements are critical for promoter activity. We determined the role of IL-6-receptor-gp130-Stat3 signaling in IL-6 activation of the gammaFBG promoter in liver and lung epithelial cells. Although IL-6 induced gammaFBG promoter activity approximately 30-fold in HepG2 cells, it was increased only 2-fold in lung A549 cells. Equivalent production of gp130 was demonstrated in both cell types by Western blotting; however, lower production of both IL-6-receptor and Stat3 explains, in part, reduced activity of the gammaFBG promoter in lung cells. Dexamethasone potentiated IL-6 induction of the gammaFBG promoter 2.3-fold in both HepG2 and A549 cells for a combined increase in promoter activity of 70-fold or 4.5-fold, respectively. Dexamethasone potentiation is likely due to the induction of IL-6-receptor expression as well as prolonged intensity and duration of Stat3 activation. By circumventing IL-6-receptor-gp130-coupled signaling with ectopic expression of the granulocyte colony-stimulating factor receptor (GCSFR)-gp130(133) chimeric receptor, overexpression of Stat3 induced gammaFBG promoter activity 30-fold in A549 cells. Together, the data suggest tissue-specific differences in IL-6-receptor-gp130-coupled signaling, thereby limiting the extent of Stat3 activation and gammaFBG expression during lung inflammation.