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Prostaglandin E2

Lipidomics Gateway (24 June 2009) [doi:10.1038/lipidmaps.2009.11]

Injury, infection and autoimmune disease can produce red and painful swelling, mediated by bioactive eicosanoids including prostaglandin E2. PGE2 signaling is also implicated in maintenance of homeostasis, and in the diverse disease processes that arise when that maintenance slips.

Prostaglandin E2 (PGE2; or 9-oxo-11R,15S-dihydroxy-5Z,13E-prostadienoic acid, to give it its systematic name) is, like all prostaglandins, a 20-carbon oxygenated lipid-signaling molecule. Prostaglandin synthesis begins with the release of arachidonic acid from phospholipids by phospholipase A2. Arachidonic acid is oxygenated by cyclooxygenase (COX) enzymes to form prostaglandin H2 (PGH2), and then other prostaglandins are derived from PGH2 by the action of specific enzymes. PGE2 synthase enzymes are microsomal PGE2 synthases 1 and 2 (mPGES1 and mPGES2) and cytosolic PGES (cPGES). Which specific enzymes are involved in producing PGE2 depends on the cell type and function; for example, although COX-2 and mPGES1 are often coupled for PGE2 synthesis, COX-1 and mPGES1 collaborate to produce PGE2 during mammary gland development 1 .

Having it all ways: PGE2 has multiple receptors

Model of prostaglandin E2. Visit PGE2 in the LIPID MAPS database for more molecular information.

PGE2 has many, often contradictory, downstream signaling consequences. These are mediated by four specific classes of E-prostanoid receptor, EP1-4. Influencing a range of pathways helps in normal maintenance of homeostasis but can make the deconstruction of disease processes more difficult. Whereas EP2 and EP4 stimulate production of cyclic AMP for example, EP3 inhibits it, and the receptors differ in their ability to be de-sensitized by ligand binding. Activation of EP1 mediates neurotoxicity in ischemic injury, whereas EP2 may be involved in the toxicity of aggregated peptides in Alzheimer's and other neurological diseases 2 3 .

Inflammatory stuff: Redness, swelling, pain and cancer

A pro-inflammatory molecule, PGE2, is involved in producing swelling, redness and pain, mediating these responses in diseases including rheumatoid arthritis. PGE2 is also involved in tumor-induced inflammation, where it is implicated in subversion of the adaptive immune response 4 (see our research highlight this month, Cancer and prostaglandin E2: Don't make it, or break it?). The huge complexity of prostaglandin signaling means that most studies have focused on specific molecules under specific situations. However, new strategies are changing that. Another paper highlighted this month (see 'Fat finding in disease: Lipids coming 'ome') describes the monitoring of production of nearly all known eicosanoids during the progression of Lyme arthritis 5 . Hopefully, global studies like this will paint a more integrated picture of prostaglandin signaling in different cell types, times and diseases.

Targeting PGE2 production: Using a shotgun instead of a scalpel?

The production of PGE2 has been targeted with inhibitors of COX-2 function to treat a range of painful and inflammatory conditions. COX-2 inhibitors have also been trialed to prevent re-occurrence of cancer. 6 . However, COX-2 products are not limited to PGE2, and the consequences of PGE2 signaling are so diverse that this approach is proving rather a blunt tool. Indeed, Merck withdrew their COX-2 inhibitor Vioxx after it was associated with increased risk of heart attacks and strokes 7 . Targeting the interaction of PGE2 with its specific receptors, or boosting its degradation, may in future offer more precise therapeutic benefits.

- Copyright © 2009 Nature Publishing Group, a division of Macmillan Publishers Limited; used with permission

References:

  1. Koller, B. H. et al. Coupling of COX-1 to mPGES1 for prostaglandin E2 biosynthesis in the murine mammary gland.

    J Lipid Res. 46, 2636-2648 (2005). doi:10.1194/jlr:M500213-JLR200

  2. Lord, A. M., North, T. E. and Zon, L. I. Prostaglandin E2: making more of your marrow.

    Cell Cycle 6, 3054-3057 (2007).

  3. Climino, P. J. herapeutic targets in prostaglandin E2 signaling for neurologic disease.

    Curr Med Chem. 15, 1863-1869 (2008).

  4. Eruslanov, E. E. Altered expression of 15-hydroxyprostaglandin dehydrogenase in tumor-infiltrated CD11b myeloid cells: a mechanism for immune evasion in cancer.

    J Immunol 182, 7548-7557 (2009). doi:10.4049/jimmunol.0802358

  5. Blaho, et al. Lipidomic analysis of dynamic eicosanoid responses during the induction and resolution of Lyme arthritis.

    J. Biol. Chem. (1 June 2009). doi:10.1074/jbc.M109.003822

  6. Yan, M. 15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors.

    Proc. Natl. Acad. Sci. USA (9 June 2009). doi:10.1073/pnas,0902367106

  7. http://www.merck.com/newsroom/vioxx/pdf/vioxx_press_release_final.pdf

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