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J Biol Chem, Vol. 275, Issue 5, 3107-3113, February 4, 2000

Transcriptional Regulation of the Cyclooxygenase-2 Gene in Activated Mast Cells^*

Srinivasa T. Reddy^§¶, David J. Wadleigh, and Harvey R. Herschman^§

From the  Molecular Biology Institute, ^§ Department of Biological Chemistry, UCLA-Los Angeles Center for the Health Sciences, Los Angeles, California 90095

Activation of mast cells by aggregation of their IgE receptors induces rapid and transient synthesis of cyclooxygenase-2 (COX-2). In this study we investigated (i) the cis-acting response elements and transcription factors active at the COX-2 promoter and (ii) the signal transduction pathways mediating COX-2 induction following aggregation of mast cell IgE receptors. Transient transfection assays with COX-2 promoter/luciferase constructs suggest that a consensus cyclic AMP response element is essential for induced COX-2 expression. Cotransfection studies with plasmids expressing c-Jun, dominant negative Ras, dominant negative c-Jun NH₂-terminal kinase, and dominant negative MEKK1 demonstrate that activation of the Ras/MEKK1/c-Jun NH₂-terminal kinase/c-Jun pathway is required for COX-2 promoter-mediated luciferase expression. Attenuation of COX-2 promoter activity by dominant negative constructs for Raf-1, ERK1, and ERK2 suggests that the Ras/Raf-1/extracellular signal-regulated kinase pathway is also necessary for COX-2 induction. Although mutating the two NF-IL6 sites individually did not affect COX-2 promoter activity, mutating both NF-IL6 sites substantially inhibits COX-2 promoter activity. Moreover, overexpression of wild type CCAAT/enhancer-binding protein- (C/EBP) augments COX-2 promoter activity in activated mast cells and cotransfection of a dominant negative C/EBP construct completely blocks COX-2 promoter/luciferase expression. Our data suggest that in activated mast cells, a Ras/MEKK1/c-Jun NH₂-terminal kinase signal transduction pathway activating c-Jun, a Ras/Raf-1/extracellular signal-regulated kinase pathway, and activated C/EBP facilitate COX-2 induction via the cyclic AMP response element and NF-IL6 sites of the COX-2 promoter.

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^* These studies were supported by National Institutes of Health NIAID and NIEHS, UCLA Asthma, Allergic, and Immunologic Diseases Center Grant AI34567.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Current address: Division of Cardiology, Dept. of Medicine, UCLA Center for the Health Sciences, 650 Charles E. Young Dr. South, Los Angeles, CA 90095.

To whom correspondence should be addressed: 341, Molecular Biology Institute, UCLA, 611 Charles E. Young Dr., East Los Angeles, CA 90095. Tel.: 310-825-8735; Fax: 310-825-1447; E-mail: hherschman@mednet.ucla.edu.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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