Prostaglandins (PG) or prostanoids are a widely distributed group of oxygenated lipids that are known to modulate cellular functions in both a physiological and pathological context. The biosynthesis of PGs is initiated through the release of arachidonic acid (AA) from cell membranes, a reaction catalysed by phospholipase A2 (PLA2). Released AA is converted to an unstable oxygenated intermediate (PGH2) by cyclooxygenase enzymes (COX1 and COX2). Once formed, the PGH2 intermediate may be converted into various prostaglandins such as prostaglandin E2 (PGE2), prostacyclin (PGI2), prostaglandin F2α (PGF2α) or prostaglandin D2 (PGD2), by a range of specific enzymes called prostaglandin synthases (1).

One of these prostaglandins, 15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2), is a natural, chemically stable but biologically active derivative of PGD2. Despite its recent discovery, 15d-PGJ2 has been shown to have multiple effects on gene and protein activities, and there is considerable evidence in the literature for a positive role for this prostaglandin; that is, restoring normal function in a wide variety of disease conditions (3). The purpose of this article is to present an overview of the actions of 15d-PGJ2 to support the hypothesis that compounds that tip the balance of prostaglandin production in favour of PGD2 and 15d-PGJ2 and away from PGE2 would have beneficial effects on a wide variety of indications where inflammation contributes to dysfunction and cell death. Consequently, 15d-PGJ2 should be a target for further therapeutic discovery and development.

15D-PGJ2 ACTIONS

The prostaglandin has a number of different actions including cytoprotection, neural repair through neurite outgrowth and active resolution of inflammation. 15d-PGJ2 exerts each of these different biological actions through its interaction with extracellular receptors and intracellular targets (1). PGD2 has been shown to bind with different affinities to two different prostaglandin D receptors (DP1 and DP2) which are present on different cell types and are coupled to different second messenger systems. On the other hand, within the cell 15d-PGJ2 has been identified as an endogenous agonist ligand for the nuclear transcription factor, peroxisome proliferator-activated receptor of the gamma subtype (PPARγ). PPARγ regulates gene expression involved in lipid regulation, inflammation, cell proliferation and cell differentiation.

PPARγ agonists such as 15d-PGJ2 repress several proinflammatory genes in activated macrophages (2), in microglial cells (3) and in human astrocytes (4). Finally, 15d-PGJ2 has activity in the cell, which is independent of PPARγ. Through covalent interaction with intracellular proteins, 15d-PGJ2 is known to activate various cell signalling pathways involved in cell protection.