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

Abstract

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 ␥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 ϳ30-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 ␥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. 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-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.

Role of STAT3 in glucocorticoid-induced expression of the human IL-10 gene

“…The interaction of glucocorticoids with STAT3 have been described earlier for the regulation of genes like fibrinogen and alpha 2 macroglobulin (Duan and Simpson-Haidaris, 2006;Lerner et al, 2003;Takeda et al, 1998). In all these cases GCs do have little activity on their own but they operate synergistically with IL-6 induced STAT3.…”

The VE‐cadherin binding domain of fibrinogen induces endothelial barrier permeability and enhances transendothelial migration of malignant breast epithelial cells

“…We have shown that lung, prostate and breast cancer epithelial cells synthesize and secrete Fg that enhances FGF-2-mediated cell proliferation, assembles into extracellular matrices and binds to cancer cell surfaces. 2,14,[32][33][34][35][36][37] In addition, others have demonstrated Fg production in adenocarcinoma cell lines of cervical 15 and intestinal 16 origin. Recent expression array profiling studies have confirmed that the Fg genes are expressed in breast 17 and lung carcinomas 18,19 isolated from patients.…”

“…The negative control peptide corresponding to fibrinopeptide A induced minimal %FITC-Dextran Flux compared with Fg or peptide b 15-42 (#p < 0.0001); however, the 13% relative fluorescence was significant (-p 5 0.001) compared with basal levels that were 1% of intact Fg-induced permeability. Peptides missing b 15-17 residues (b [18][19][20][21][22][23][24][25][26][27][28][29][30][31] or b [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] ) or truncated at the C-terminus (b [15][16][17][18][19][20][21][22][23][24][25][26][27] (Fig. 2c).…”

“…14,[26][27][28] Control experiments indicated that Fg added to breast cancer or endothelial cells was not processed further by protease degradation or crosslinking to higher ordered structures (data not shown). Synthetic peptides corresponding to the Fg b-chain primary structure were custom synthesized as previously described, 11 and include b , b [15][16][17][18][19][20][21][22][23][24][25][26][27] , b 18-31 and b [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] (Table I). Fibrinopeptide A (Bachem) was used as a nonspecific peptide for permeability studies.…”

The simultaneous occurrence of both hypercoagulability and hypofibrinolysis in blood and serum during systemic inflammation, and the roles of iron and fibrin(ogen)

“…One important mechanism involving the (IL-1-mediated) activation of IL-6 that in turn induces fibrinogen synthesis by hepatocytes [484][485][486] and other cells 482,[487][488][489][490] is especially pertinent. IL-6 is also involved in iron (dys)regulation, in particular by its ability to induce hepcidin biosynthesis (e.g.…”