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J. Biol. Chem., Vol. 281, Issue 18, 12451-12457, May 5, 2006

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

Hai Ou Duan and Patricia J. Simpson-Haidaris^¶1

From the Departments of Medicine/Hematology-Oncology Division, Pathology and Laboratory Medicine, and ^¶Microbiology and Immunology, University of Rochester School of Medicine and Dentistry Rochester, New York 14642

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 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 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-receptor-gp130-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.

Received for publication, January 11, 2006 , and in revised form, March 7, 2006.

^* This work was supported by Grants R01-HL50616 and P01-HL30616 from NHLBI, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Medicine/Hematology-Oncology Division, P.O. Box 610, 601 Elmwood Ave., Rochester, NY 14642. Tel.: 585-275-8267; Fax: 585-473-4314; E-mail: pj_simpsonhaidaris{at}urmc.rochester.edu.

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