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Research ArticleArticle

Mechanisms of Prostaglandin E2 Release by Intact Cells Expressing Cyclooxygenase-2: Evidence for a ‘Two-Component’ Model

Michael A. Saunders, Maria G. Belvisi, Guiseppe Cirino, P. J. Barnes, Timothy D. Warner and Jane A. Mitchell
Journal of Pharmacology and Experimental Therapeutics March 1999, 288 (3) 1101-1106;
Michael A. Saunders
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Maria G. Belvisi
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Guiseppe Cirino
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P. J. Barnes
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Timothy D. Warner
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Jane A. Mitchell
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Abstract

Prostaglandin (PG) release in cells expressing constitutive cyclooxygenase-1 is known to be regulated by liberation of arachidonic acid by phospholipase A2 followed by metabolism by cyclooxygenase. However, the relative contribution of phospholipase A2 to the release of PGs in cells expressing cyclooxygenase-2 is not clear. We addressed this question by using radioimmunoassay to measure PGE2 release by human cells (A549) induced to express cyclooxygenase-2 (measured by Western blot analysis) by interleukin-1β. Cells were either unstimulated or stimulated with agents known to activate phospholipase A2(bradykinin, Des-Arg10-kallidin, or the calcium ionophore A23187) or treated with exogenous arachidonic acid. When cells were treated to express cyclooxygenase-2, the levels of PGE2released over 15 min were undetectable; however, in the same cells stimulated with bradykinin, A23187, or arachidonic acid, large amounts of prostanoid were produced. Using selective inhibitors/antagonists, we found that the effects of bradykinin were mediated by B2 receptor activation and that prostanoid release was due to cyclooxygenase-2, and not cyclooxygenase-1, activity. In addition, we show that the release of PGE2 stimulated by either bradykinin, A23187, or arachidonic acid was inhibited by the phospholipase A2 inhibitor arachidonate trifluoromethyl ketone. Hence, we have demonstrated that PGE2 is released by two components: induction of cyclooxygenase-2 and supply of substrate, probably via activation of phospholipase A2. This is illustrated in A549 cells by a clear synergy between the cytokine interleukin-1β and the kinin bradykinin.

Footnotes

  • Send reprint requests to: Dr. Jane A. Mitchell, Ph.D, Unit of Critical Care Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, United Kingdom. E-mail: j.mitchell{at}rbh.nthames.nhs.uk

  • ↵1 This work was supported by grants from the British Lung Foundation (to M.A.S.), Wellcome Trust (to B.M.G. and J.A.M.), British Heart Foundation (to T.D.W.), and Boehringer Ingelheim Pharma KG (to T.D.W.). Jane A. Mitchell is a Wellcome Career Development Fellow. A preliminary account of this work was presented at the British Pharmacological Society meeting (Saunders et al., 1996).

  • ↵2 Present address: Thoracic Medicine, Imperial College School of Medicine, National Heart and Lung Institute, Dovehouse Street, London, England SW3 6LY.

  • ↵3 Present address: Pharmacology Department, Rhone-Poulenc Rorer Research and Development, Dagenham Research Center, Rainham Road South, Dagenham, Essex, England RM10 7XS.

  • ↵4 Present address: Department of Pharmacology, University of Naples, Via Domenico Montesano, 49 80131 Napoli, Italy.

  • ↵5 Present address: Vascular Inflammation, The William Harvey Research Institute, Saint Bartholomew’s and the Royal London School of Medicine and Dentistry, Charterhouse Square, London, England EC1M 6BQ.

  • ↵6 Present address: Unit of Critical Care Medicine, Royal Brompton Hospital, Imperial College School of Medicine at the National Heart and Lung Institute, Sydney Street, London, England SW3 6NP.

  • Abbreviations:
    COX
    cyclooxygenase
    PLA2
    phospholipase A2
    PG
    prostaglandin
    IL-1β
    interleukin-1β
    AACOCF3
    arachidonate trifluoromethyl ketone
    PACOCF3
    palmitoyl trifluoromethyl ketone
    • Received April 23, 1998.
    • Accepted October 2, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 3
1 Mar 1999
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Research ArticleArticle

Mechanisms of Prostaglandin E2 Release by Intact Cells Expressing Cyclooxygenase-2: Evidence for a ‘Two-Component’ Model

Michael A. Saunders, Maria G. Belvisi, Guiseppe Cirino, P. J. Barnes, Timothy D. Warner and Jane A. Mitchell
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 1101-1106;

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Research ArticleArticle

Mechanisms of Prostaglandin E2 Release by Intact Cells Expressing Cyclooxygenase-2: Evidence for a ‘Two-Component’ Model

Michael A. Saunders, Maria G. Belvisi, Guiseppe Cirino, P. J. Barnes, Timothy D. Warner and Jane A. Mitchell
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 1101-1106;
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