Cell Type-specific Differential Induction of the Human -Fibrinogen Promoter by Interleukin-6*

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 magnitudeof Stat3 binding to three IL-6motifs on thehuman FBG 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 FBG promoter in liver and lung epithelial cells. Although IL-6 induced FBG promoter activity 30-fold in HepG2 cells, it was increased only 2-fold in lung A549 cells. Equivalent production of gp130was demonstrated in both cell types byWestern blotting; however, lower production of both IL-6receptor and Stat3 explains, in part, reduced activity of the FBG promoter in lung cells. Dexamethasone potentiated IL-6 induction of the FBG 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.Dexamethasonepotentiation 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-receptorgp130-coupled signaling with ectopic expression of the granulocyte colony-stimulating factor receptor (GCSFR)-gp130(133) chimeric receptor, overexpression of Stat3 induced FBG 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 FBG expression during lung inflammation.