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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-2gene in response to endotoxin and other pro-inflammatory stimuli. We report that the induction of COX-2expression by lipopoly-saccharide (LPS) and pro-inflammatory cytokines correlates with ESE-1 induction in monocyte⁄macrophages. . | iFEBS Journal 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 IsraelDeaconess MedicalCenter and Harvard Medical School Boston USA Keywords COX-2 ESE-1 Ets gene expression LPS Correspondence T. A. Libermann New England Baptist Bone Joint Institute Department of Medicine Beth IsraelDeaconess MedicalCenter Harvard Institutes of Medicine 4 Blackfan Circle Boston MA 02115 USA Fax 1 617 975 5299 Tel 1 617 667 3393 E-mail tliberma@bidmc.harvard.edu 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 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-KB .
