Trends in Immunology
ReviewProstaglandins as modulators of immunity
Section snippets
Prostaglandins
Prostaglandins are small lipid molecules that regulate numerous processes in the body, including kidney function, platelet aggregation, neurotransmitter release and modulation of immune function 1, 2. The production of prostaglandins begins with the liberation of arachidonic acid from membrane phospholipids by phospholipase A2 in response to inflammatory stimuli. Arachidonic acid is converted to PGH2 by the cyclooxygenase enzymes COX-1 and COX-2 (known formally as prostaglandin endoperoxide H
PGE2
One of the best known and most well-studied prostaglandins is PGE2. PGE2 is produced by many cells of the body – including fibroblasts, macrophages and some types of malignant cells – and exerts its actions by binding to one (or a combination) of its four subtypes of receptor (EP1, EP2, EP3 and EP4). In the mouse, the EP3 subtype consists of three different isoforms, termed α, β and γ, and there are seven EP3 splice variants in humans identified to date. The receptors are rhodopsin-type
PGE2 in disease
PGE2 plays an integral role in a myriad of infections and diseases. We have chosen to highlight two diseases for which PGE2 has been shown to be central to disease progression – periodontal disease and certain cancers.
15-deoxy-Δ12,14-PGJ2
The J series of prostaglandins, once thought to comprise inactive degradation products of PGD2, is now well established as regulating diverse processes, such as adipogenesis, inflammation and tumorigenesis. 15-d-PGJ2 is the end-product metabolite of PGD2 and is produced by a variety of cells, including mast cells, T cells, platelets and alveolar macrophages. The exact mechanism of entry of 15-d-PGJ2 into cells is unknown, but it is possible that 15-d-PGJ2 enters by an active transport system
15-deoxy-Δ12,14-PGJ2 in disease
Although 15-d-PGJ2 is implicated in the regulation of many immune functions and disorders, here, we focus on the role of this lipid in inflammation and cancer.
Conclusions
The roles of PGE2 and 15-d-PGJ2 in the immune system are diverse and complex. Both mediators have profound, and opposing, effects on tumorigenesis and are key regulators of inflammation. Owing to the fact that these two lipids are produced from the same precursor (arachidonic acid) by the same cyclooxygenase enzymes, additional means to regulate the production of one or the other prostaglandin must exist. Prime candidates are the prostaglandin synthases, which synthesize specific prostaglandins
Acknowledgements
This research was supported by USPHS grants DE11390, HL56002, HL007216, 5-T32DE07061-21, T32HL66988, ES01247 and EY08976, the James P. Wilmot Cancer Center Discovery Fund and Cystic Fibrosis Foundation grant CFF0020.
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