The Ets transcription factor ESE-1 mediates induction of the COX-2 gene by LPS in monocytes
Department of Medicine, Division of Rheumatology
Medical Subject Headings
Animals; Base Sequence; Cyclooxygenase 2; DNA-Binding Proteins; Enzyme Induction; Humans; Lipopolysaccharides; Membrane Proteins; Mice; Molecular Sequence Data; Monocytes; Mutation; NFATC Transcription Factors; Nuclear Proteins; Promoter Regions, Genetic; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ets; Transcription Factors
Cellular and Molecular Physiology | Genetics | Musculoskeletal Diseases | Rheumatology | Skin and Connective Tissue Diseases
Cyclooxygenase-2 (COX-2) is a key enzyme in the production of prostaglandins that are major inflammatory agents. COX-2 production is triggered by exposure to various cytokines and to bacterial endotoxins. We present here a novel role for the Ets transcription factor ESE-1 in regulating the COX-2 gene in response to endotoxin and other pro-inflammatory stimuli. We report that the induction of COX-2 expression by lipopolysaccharide (LPS) and pro-inflammatory cytokines correlates with ESE-1 induction in monocyte/macrophages. ESE-1, in turn, binds to several E26 transformation specific (Ets) sites on the COX-2 promoter. In vitro analysis demonstrates that ESE-1 binds to and activates the COX-2 promoter to levels comparable to LPS-mediated induction. Moreover, we provide results showing that the induction of COX-2 by LPS may require ESE-1, as the mutation of the Ets sites in the COX-2 promoter or overexpression of a dominant-negative form of ESE-1 inhibits LPS-mediated COX-2 induction. The effect of ESE-1 on the COX-2 promoter is further enhanced by cooperation with other transcription factors such as nuclear factor-kappa B and nuclear factor of activated T cells. Neutralization of COX-2 is the goal of many anti-inflammatory drugs. As an activator of COX-2 induction, ESE-1 may become a target for such therapeutics as well. Together with our previous reports of the role of ESE-1 as an inducer of nitric oxide synthase in endothelial cells and as a mediator of pro-inflammatory cytokines in vascular and connective tissue cells, these results establish ESE-1 as an important player in the regulation of inflammation.
Rights and Permissions
Citation: FEBS J. 2005 Apr;272(7):1676-87. Link to article on publisher's site
Grall, Franck T.; Prall, Wolf C.; Wei, Wanjiang; Gu, Xuesong; Cho, Je-Yoel; Choy, Bob K.; Zerbini, Luiz F.; Inan, Mehmet S.; Goldring, Steven R.; Gravallese, Ellen M.; Goldring, Mary B.; Oettgen, Peter; and Libermann, Towia A., "The Ets transcription factor ESE-1 mediates induction of the COX-2 gene by LPS in monocytes" (2005). Rheumatology Publications and Presentations. 41.