Tài liệu Báo cáo khoa học: The Ets transcription factor ESE-1 mediates induction of the COX-2 gene

The Ets transcription factor ESE-1 mediates induction

of the COX-2 gene by LPS in monocytes

Franck T. Grall, Wolf C. Prall, Wanjiang Wei, Xuesong Gu, Je-Yoel Cho, Bob K. Choy,

Luiz F. Zerbini, Mehmet S. Inan, Steven R. Goldring, Ellen M. Gravallese, Mary B. Goldring,

Peter Oettgen and Towia A. Libermann

New England Baptist Bone and Joint Institute and BIDMC Genomics Center, Beth Israel Deaconess Medical Center and Harvard Medical

School, Boston, USA

Cyclooxygenase (COX) is an enzyme that converts

arachidonic acid into the prostaglandin H2. This prod￾uct is the critical point of the synthetic pathway of

numerous members of the prostaglandin family. COX

exists as two major isoforms derived from two separate

genes: COX-1 and COX-2. COX-1 is constitutively

expressed, whereas COX-2 expression is inducible.

Pro-inflammatory substances are some of the major

activators of COX-2. Examples include interleukin

(IL)-1 [1], tumor necrosis factor (TNF)-a [2], and bac￾terial lipopolysaccharide (LPS) [3]. A third isoform

COX-3 has also been reported [4].

The mechanisms leading to COX-2 expression

involve various combinations of different transcription

factors, depending on the cell type and stimulus. The

members of the C ⁄EBP family have been identified as

Keywords

COX-2; ESE-1; Ets; gene expression; LPS

Correspondence

T. A. Libermann, New England Baptist Bone

& Joint Institute, Department of Medicine,

Beth Israel Deaconess Medical Center,

Harvard Institutes of Medicine, 4 Blackfan

Circle, Boston, MA 02115, USA

Fax: +1 617 975 5299

Tel: +1 617 667 3393

E-mail: [email protected]

(Received 21 July 2004, revised 19 January

2005, accepted 2 February 2005)

doi:10.1111/j.1742-4658.2005.04592.x

Cyclooxygenase-2 (COX-2) is a key enzyme in the production of prosta￾glandins that are major inflammatory agents. COX-2 production is trig￾gered by exposure to various cytokines and to bacterial endotoxins. We

present here a novel role for the Ets transcription factor ESE-1 in regula￾ting the COX-2 gene in response to endotoxin and other pro-inflammatory

stimuli. We report that the induction of COX-2 expression by lipopoly￾saccharide (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-jB

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 syn￾thase 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.

Abbreviations

Ad, Adenovirus; ChIP, chromatin immunoprecipitation; CMV, cytomegalovirus; COX, cyclooxygenase; CRE, cAMP responsive element;

ESE, epithelium specific Ets factor; Ets, E26 transformation specific; GAPDH, glyceraldehydes-3-phosphate dehydrogenase; HRP,

horseradish peroxidase; ICAM, intercellular adhesion molecule; IL, interleukin; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide;

MMP, matrix metalloproteinase; NFAT, nuclear factor of activated T cells; NF-jB, nuclear factor-jB; TNF, tumor necrosis factor.

1676 FEBS Journal 272 (2005) 1676–1687 ª 2005 FEBS