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

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‐κB 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.