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J. Biol. Chem., Vol. 278, Issue 50, 49954-49964, December 12, 2003

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Cyclooxygenase-2 Induction by Bradykinin in Human Pulmonary Artery Smooth Muscle Cells Is Mediated by the Cyclic AMP Response Element through a Novel Autocrine Loop Involving Endogenous Prostaglandin E₂, E-prostanoid 2 (EP2), and EP4 Receptors^*

Dawn A. Bradbury, Robert Newton, Yong M. Zhu, Hala El-Haroun, Lisa Corbett, and Alan J Knox¶

From the Division of Respiratory Medicine, University of Nottingham, City Hospital, Nottingham NG5 1PB, United Kingdom and Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College School of Medicine, London SW3 6LY, United Kingdom

Bradykinin (BK) is an important mediator in several inflammatory and vascular diseases that acts in part via induction of cyclooxygenase-2 (COX-2). The mechanisms involved in BK-mediated COX-2 induction are unclear. Here we characterized the transcriptional mechanisms involved in human pulmonary artery smooth muscle cells. BK stimulated the activity of a transiently transfected 966-bp (–917 to + 49) COX-2 promoter luciferase reporter construct. There was no reduction in BK-induced luciferase activity in cells transfected with COX-2 promoter constructs of 674, 407, 239, and 135 bp or constructs with mutated CCAAT/enhancer-binding protein- or NF-B-binding sites. In contrast luciferase activity was reduced in cells transfected with a 407-bp COX-2 promoter fragment containing a mutated cAMP response element (CRE)-binding site, suggesting that the CRE binding site is critical. Electrophoretic mobility shift assays using oligonucleotides specific for the CRE-binding region of the COX-2 promoter and consensus oligonucleotides showed strong specific binding. Furthermore BK increased consensus cAMP-responsive luciferase reporter (p6CRE/luc)-mediated luciferase expression. CRE activation occurred by BK inducing cytosolic phospholipase A₂-mediated arachidonic acid release and rapid prostaglandin E₂ (PGE₂) production, thereby increasing cAMP. Indomethacin inhibited BK-induced PGE₂ production, cAMP accumulation, and CRE/luc reporter and COX-2 promoter luciferase activity. Exogenous PGE₂ and EP2 (ONO-AE1 259) and EP4 (ONO-AE1 329) PGE₂ receptor agonists mimicked the effect of BK. Collectively these studies indicate that COX-2 induction by BK in human pulmonary artery smooth muscle cells is mediated by the CRE through a novel autocrine loop involving endogenous PGE₂.

Received for publication, July 22, 2003 , and in revised form, September 25, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Div. of Respiratory Medicine, Clinical Science Bldg., City Hospital, Hucknall Rd., Nottingham NG5 1PB, UK. Tel.: 44-115-8404775; Fax: 44-115-8404771; E-mail: alan.knox{at}nottingham.ac.uk.

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