Journal of Biological Chemistry
Volume 276, Issue 52, 28 December 2001, Pages 48693-48701
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GENES: STRUCTURE AND REGULATION
The Induction of Cyclooxygenase-2 mRNA in Macrophages Is Biphasic and Requires both CCAAT Enhancer-binding protein β (C/EBPβ) and C/EBPδ Transcription Factors*

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Prostaglandins are important mediators of activated macrophage functions, and their inducible synthesis is mediated by cyclooxygenase-2 (COX-2). Here, we make use of the murine macrophage cells RAW264 as well as of immortalized macrophages derived from mice deficient for the transcription factor CCAAT enhancer-binding protein β (C/EBPβ) to explore the molecular mechanisms regulating COX-2 induction in activated macrophages. We demonstrate that lipopolysaccharide-mediated COX-2 mRNA induction is biphasic. The initial phase is independent of de novo protein synthesis, correlates with cAMP-response element-binding protein (CREB) activation, is inhibited by treatments that abolish CREB phosphorylation and reduce NF-κB-mediated gene activation, and requires the presence of the transcription factor C/EBPβ. On the other hand, C/EBPδ appears to be essential in addition to C/EBPβ to effect the second phase of COX-2 gene transcription, which is important for maintaining the induced state and requires de novo protein synthesis. Indeed, both phases of COX-2 induction were defective in C/EBPβ−/− macrophages. Moreover, the synthesis of C/EBPδ was increased dramatically by treatment with lipopolysaccharide and, like COX-2 induction, repressed by combined inhibition of the MAPK and of the SAPK2/p38 cascades. Taken together, these data identify CREB, NF-κB, and both C/EBPβ and -δ as key factors in coordinately orchestrating transcription from the COX-2 promoter in activated macrophages.

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Published, JBC Papers in Press, October 19, 2001, DOI 10.1074/jbc.M108282200

*

This work was supported by the Wellcome Trust (Senior Research Fellowship to V. P.), the UK Medical Research Council (to M. C.), The Royal Society of London, and the Louis Jeantet Foundation (to P. C.).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.

Recipient of an EC Marie Curie fellowship.