RT Journal Article
SR Electronic
T1 Polarization of the Innate Immune Response by Prostaglandin E2: a Puzzle of Receptors and Signals
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.113.089573
DO 10.1124/mol.113.089573
A1 Mario Rodriguez
A1 Esther Domingo
A1 Cristina Municio
A1 Yolanda Alvarez
A1 Etzel Hugo
A1 Nieves Fernandez
A1 Mariano Sanchez Crespo
YR 2013
UL http://molpharm.aspetjournals.org/content/early/2013/10/29/mol.113.089573.abstract
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.