Cell type-specific differential induction of the human gamma-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 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.
Duan
Hai Ou
HO
Department of Medicine/Hematology-Oncology Division, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
Simpson-Haidaris
Patricia J
PJ
D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005340:Fibrinogen / Q000235:genetics*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation
D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050822:Cytokine Receptor gp130; D003907:Dexamethasone; D005340:Fibrinogen