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Inducible cyclooxygenase may have anti-inflammatory properties

Abstract

Cyclooxygenase (COX) has two isoforms. Generally, COX 1 is constitutively expressed in most tissues, where it maintains physiological processes1; inducible COX 2 is considered a pro-inflammatory enzyme and a chief target for the treatment of inflammatory diseases2. Here we present evidence that COX 2 may have anti-inflammatory properties. In carrageenin-induced pleurisy in rats, the predominant cells at 2 hours are polymorphonuclear leucocytes, whereas mononuclear cells dominate from 24 hours until resolution at 48 hours3. In this model, COX 2 protein expression peaked initially at 2 hours, associated with maximal prostaglandin E2 synthesis. However, at 48 hours there was a second increase in COX 2 expression, 350% greater than that at 2 hours. Paradoxically, this coincided with inflammatory resolution and was associated with minimal prostaglandin E2 synthesis. In contrast, levels of prostaglandin D2, and 15deoxyΔ12,13,14prostaglandin J2 were high at 2 hours, decreased as inflammation increased, but were increased again at 48 hours. The selective COX 2 inhibitor NS-398 and the dual COX 1/COX 2 inhibitor indomethacin inhibited inflammation at 2 hours but significantly exacerbated inflammation at 48 hours. This exacerbation was associated with reduced exudate prostaglandin D2 and 15deoxyΔ12,13,14prostaglandin J2 concentrations, and was reversed by replacement of these prostaglandins. Thus, COX 2 may be pro-inflammatory during the early phase of a carrageenin-induced pleurisy, dominated by polymorphonuclear leucocytes, but may aid resolution at the later, mononuclear cell-dominated phase by generating an alternative set of anti-inflammatory prostaglandins.

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Figure 1: Correlation between inflammation, COX 2 expression, COX activity and PGE2 levels in carrageenin-induced pleurisy.
Figure 2: Effects of COX inhibitors on inflammatory exudate volume and total cell numbers.
Figure 3: The role of PGD2 and 15deoxyΔ12–14PGJ2 in carrageenin-induced pleurisy.

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Acknowledgements

The authors acknowledge the support of the following organizations: D.W.G., The Hyal Research Foundation, Canada; P.R.C.-N., The Joint Research Board of the Special Trustees of St. Bartholomew's Hosptial, London, UK and the Arthritis Research Campaign, UK; D.W., Oliver Bird Fund, Nuffield Foundation, UK.

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Correspondence to P.R. Colville-Nash.

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Gilroy, D., Colville-Nash, P., Willis, D. et al. Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med 5, 698–701 (1999). https://doi.org/10.1038/9550

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