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J. Biol. Chem., Vol. 278, Issue 42, 41270-41281, October 17, 2003

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Functional Analysis of Interleukin 6 Response Elements (IL-6REs) on the Human -Fibrinogen Promoter

BINDING OF HEPATIC Stat3 CORRELATES NEGATIVELY WITH TRANSACTIVATION POTENTIAL OF TYPE II IL-6REs^*

Hai Ou Duan   and Patricia J. Simpson-Haidaris   ¶ ||

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

Several families of transcription factors play important roles in modulating liver-specific gene expression during an acute phase response (APR). Stat3/APR factor is the main transactivator of gene expression by the interleukin (IL)-6 family of cytokines signaling through gp130. During an APR, fibrinogen (FBG) genes are coordinately up-regulated by IL-6 and glucocorticoids. Except for rat FBG, attempts to demonstrate direct binding of IL-6-activated Stat3 to FBG CTGGGAA promoter elements have not been successful. Herein we show the presence of three functional type II IL-6 response elements (IL-6REs) on the human FBG promoter and that the magnitude of Stat3 binding to these elements correlates negatively with their functional activity in reporter gene assays. Stat3-specific binding to FBG IL-6REs was confirmed by cross-competition with ₂-macroglobulin IL-6RE and specific interactions with anti-Stat3 in electrophoretic mobility shift assays. All type II IL-6REs contributed to full promoter activity; however, transactivation from Site II at –306 to –301 was strongest. In contrast to a previous report, IL-6 failed to induce activation of serum amyloid A-activating factor-1/c-Myc-associated zinc finger protein (SAF-1/MAZ), and mutation of the SAF-1RE had little effect on IL-6 induction of FBG promoter activity. In the absence of a functional glucocorticoid receptor response element, dexamethasone potentiated IL-6-induced FBG promoter activity 2-fold, requiring promoter-proximal Site I and Site II; the promoter-distal Site III had no effect on dexamethasone potentiation of IL-6-induced promoter activity. Notably the propensity for Stat3 binding to human FBG IL-6REs was low compared with Stat3 binding to the ₂-macroglobulin IL-6RE. Together these data suggest that Stat3 transactivation via IL-6REs on FBG promoters likely involves participation of additional transcription factors and/or coactivators to achieve optimal coordinated up-regulation during an APR.

Received for publication, April 22, 2003 , and in revised form, July 31, 2003.

^* This work was supported by NHLBI, National Institutes of Health Grants PO1-HL30616 (Project 2 and Core B) and RO1-HL50615 (to P. J. S.-H.). 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.

^|| To whom correspondence should be addressed: Dept. of Medicine/Hematology-Oncology Unit, Program in Hemostasis and Thrombosis, 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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