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The cardinal role of the phospholipase A2/cyclooxygenase-2/prostaglandin E synthase/prostaglandin E2 (PCPP) axis in inflammostasis

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Abstract

The process of inflammation is regulated in part by bioactive lipids of which prostaglandins/eicosanoids form an important class. We provide evidence that the phospholipase A2/cyclooxygenase-2/prostaglandin E synthase/prostaglandin E2 (PCPP) axis is positioned at the core of a natural regulatory circuit controlling the initiation, magnitude, duration, and resolution of the inflammatory response. During the inflammatory phase, proinflammatory cytokine, chemokine and matrix destructive metalloprotease expression levels are moderated by the PCPP axis through the modulation of signaling pathways that control proinflammatory gene expression at transcriptional, post-transcriptional, and translational levels. The PCPP axis also contributes to the activation of lipid mediator class switching; this highly coordinated process results in the biosynthesis of lipoxins and resolvins that promote inflammatory resolution through a variety of cellular and molecular mechanisms. The PCPP axis activity is autoregulated by way of a positive feedback circuit involving PGE2-mediated, p38 MAPK-dependent stabilization of COX-2 mRNA and COX-2 catalytic potentiation via its limited proteolytic cleavage (e.g., Ca2+-activated calpains). In conclusion, through its fine temporal modulation of multiple signaling cassettes via EP1-EP4 GPCRs, PGE2 influences the onset, course, magnitude, and duration of the inflammatory response and functions as a key feedback regulator of the cellular and molecular processes controlling inflammation.

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Notes

  1. Other enzymes also participate in the production of PGE2. Under basal (i.e., non-inflammatory) conditions, the constitutively and ubiquitously expressed COX-1 isoform catalyzes the rate-limiting step in PGE2 biosynthesis. Basal PGE2 production is required for homeostatic purposes (in the kidney and gastrointestinal tract, for example). The ubiquitous and constitutively expressed cytosolic prostaglandin E synthase (cPGES) preferentially couples to COX-1 for basal PGE2 biosynthesis. Interestingly, a third PGE synthase, namely mPGES-2, has been shown to couple to both COX isoforms with a modest preference for COX-2 [14]. It has been inferred that mPGES-2 may contribute to PGE2 production during the resolution phase of inflammation [15] and/or to homeostatic PGE2 biosynthesis.

  2. Fibroblast-like cells of the synovial membrane. These cells are central orchestrators of rheumatoid arthritis (RA) pathophysiology and a principal source of COX-2/PGE2 axis activity in the RA joint. Synovial fibroblast activation is a defining step in the development of RA as it leads to the formation of the hyperplastic, bone- and cartilage-eroding pannus.

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, McGill University, 3640 University St, Montreal, QC, H3A 2B2, Canada

    A. D. Mancini

  2. Department of Medicine, McGill University, 687 Pine Ave, Montreal, QC, H3A 1A1, Canada

    J. A. Di Battista

  3. CRCHUM, Technopôle Angus, 2901 Rachel Street East, Room 323, Montreal, QC, H1W 4A4, Canada

    A. D. Mancini

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  1. A. D. Mancini
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  2. J. A. Di Battista
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Correspondence to A. D. Mancini.

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Mancini, A.D., Di Battista, J.A. The cardinal role of the phospholipase A2/cyclooxygenase-2/prostaglandin E synthase/prostaglandin E2 (PCPP) axis in inflammostasis. Inflamm. Res. 60, 1083–1092 (2011). https://doi.org/10.1007/s00011-011-0385-7

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  • DOI: https://doi.org/10.1007/s00011-011-0385-7

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