Title

The Ets transcription factor ESE-1 mediates induction of the COX-2 gene by LPS in monocytes

UMMS Affiliation

Department of Medicine, Division of Rheumatology

Date

4-2005

Document Type

Article

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

Disciplines

Cellular and Molecular Physiology | Genetics | Musculoskeletal Diseases | Rheumatology | Skin and Connective Tissue Diseases

Abstract

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

Comments

At the time of publication, Ellen Gravallese was not yet affiliated with the University of Massachusetts Medical School

Related Resources

Link to Article in PubMed

PubMed ID

15794755