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-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.
Grall
Franck T
FT
New England Baptist Bone and Joint Institute and BIDMC Genomics Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Prall
Wolf C
WC
Wei
Wanjiang
W
Gu
Xuesong
X
Cho
Je-Yoel
JY
Choy
Bob K
BK
Zerbini
Luiz F
LF
Inan
Mehmet S
MS
Goldring
Steven R
SR
Gravallese
Ellen M
EM
Goldring
Mary B
MB
Oettgen
Peter
P
Libermann
Towia A
TA
D000818:Animals; D001483:Base Sequence; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction / Q000502:physiology*; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism*; D009154:Mutation; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C105529:ELF3 protein, human; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases