PT  - JOURNAL ARTICLE
AU  - Mario Rodriguez
AU  - Esther Domingo
AU  - Cristina Municio
AU  - Yolanda Alvarez
AU  - Etzel Hugo
AU  - Nieves Fernandez
AU  - Mariano Sanchez Crespo
TI  - Polarization of the Innate Immune Response by Prostaglandin E2: a Puzzle of Receptors and Signals
AID  - 10.1124/mol.113.089573
DP  - 2013 Jan 01
TA  - Molecular Pharmacology
PG  - mol.113.089573
4099  - http://molpharm.aspetjournals.org/content/early/2013/10/29/mol.113.089573.short
4100  - http://molpharm.aspetjournals.org/content/early/2013/10/29/mol.113.089573.full
AB  - Eicosanoids tailor the innate immune response by supporting local inflammation and exhibiting immunomodulatory properties. Prostaglandin E2 (PGE2) is the most abundant eisosanoid in the inflammatory milieu due to the robust production elicited by pathogen-associated molecular patterns on cells of the innate immune system. The different functions and cell distribution of E prostanoid (EP) receptors explain the difficulty so far encountered to delineate the actual role of PGE2 in the immune response. The biosynthesis of eicosanoids includes as the first step the Ca2+- and kinase-dependent activation of the cytosolic phospholipase A2, which releases arachidonic acid from membrane phospholipids, and later events depending on the transcriptional regulation of the enzymes of the cyclooxygenase routes, where PGE2 is the most relevant product. Acting in an autocrine/paracrine manner in macrophages, PGE2 induces a regulatory phenotype including the expression of IL-10, sphingosine kinase 1, and the TNF family molecule LIGHT. PGE2 also stabilizes the suppressive function of myeloid-derived suppressor cells, inhibits the release of IL-12 p70 by macrophages and dendritic cells, and may enhance the production of IL-23. PGE2 is a central component of the inflammasome-dependent induction of the eicosanoid storm that leads to massive loss of intravascular fluid, increases the mortality rate associated with coinfection by Candida ssp. and bacteria, and inhibits fungal phagocytosis. These effects have important consequences for the outcome of infections and the polarization of the immune response into the Th2 and Th17 types and can be a clue to develop pharmacological tools to address infectious, autoimmune, and autoinflammatory diseases.