Polarization of the Innate Immune Response by Prostaglandin E₂: A Puzzle of Receptors and Signals

Abstract

Eicosanoids tailor the innate immune response by supporting local inflammation and exhibiting immunomodulatory properties. Prostaglandin (PG) E 2 is the most abundant eicosanoid 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 receptors explain the difficulty encountered thus far to delineate the actual role of PGE 2 in the immune response. The biosynthesis of eicosanoids includes as the first step the Ca 21 -and kinase-dependent activation of the cytosolic phospholipase A 2 , which releases arachidonic acid from membrane phospholipids, and later events depending on the transcriptional regulation of the enzymes of the cyclooxygenase routes, where PGE 2 is the most relevant product. Acting in an autocrine/ paracrine manner in macrophages, PGE 2 induces a regulatory phenotype including the expression of interleukin (IL)-10, sphingosine kinase 1, and the tumor necrosis factor family molecule LIGHT. PGE 2 also stabilizes the suppressive function of myeloidderived suppressor cells, inhibits the release of IL-12 p70 by macrophages and dendritic cells, and may enhance the production of IL-23. PGE 2 is a central component of the inflammasomedependent 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 T helper cell types 2 and 17 and can be a clue to develop pharmacological tools to address infectious, autoimmune, and autoinflammatory diseases.

Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells

“…1A). Consistent with the established role of EP2/EP4 prostanoid receptor signaling in promoting IL-10 expression in myeloid cells (19), differentiation of BMDCs in the presence of PGE 2 increased levels of IL-10 detectable in the culture media by ELISA following stimulation with a variety of microbial-derived ligands (Fig. S1A).…”

“…In addition to the PKA-CREB cascade, cAMP activates scaffolding proteins, called exchange proteins activated by cAMP (EPACs), that nucleate MAP kinase and cytoskeletal signaling components (32). Of note, the stimulatory effects of PGE 2 on IL-23 and NO production have both been linked to the cAMP-EPAC pathways in myeloid cells (19). Hence, our findings extend previous studies of SIK inhibitors by suggesting a model in which SIK inhibition promotes selective enhancement of CREB-dependent Il10 expression in the absence of pleiotropic effects of elevated intracellular cAMP (Fig.…”

“…For instance, disruption of signaling pathways linking microbial recognition receptors to NF-κB activation with small-molecule inhibitors of protein kinase C (PKC) or glycogen synthase kinase-3β (GSK-3β) up-regulates IL-10 production by lipopolysaccharide (LPS)-stimulated MΦs (17,18). Conversely, CREB activation by EP2/EP4 prostanoid receptor agonists like prostaglandin E 2 (PGE 2 ) promotes IL-10 production by myeloid cells (19). Recently, salt-inducible kinases (SIKs), which are members of the AMP-activated protein kinase family, have been identified as a key component of the CREB activation cascade (20,21).…”

PGE2 induced in and released by dying cells functions as an inhibitory DAMP

“…PGE2 is an eicosanoid lipid mediator that can exert various effects including cell proliferation, stem cell expansion, and immunosuppression (11). PGE2 is the main product of two cyclooxygenases, COX-1 and COX-2, of which COX-1 is constitutively expressed and COX-2 is induced by various stimuli such as cytokines and various PAMPs (12,13). PGE2 is the most abundant eicosanoid lipid in the inflammatory environment, and its receptors EP2 and EP4 and their downstream signaling to cAMP are proposed for the suppression of inflammation, although the precise mechanism is unclear (10,12,(14)(15)(16).…”

“…PGE2 is the main product of two cyclooxygenases, COX-1 and COX-2, of which COX-1 is constitutively expressed and COX-2 is induced by various stimuli such as cytokines and various PAMPs (12,13). PGE2 is the most abundant eicosanoid lipid in the inflammatory environment, and its receptors EP2 and EP4 and their downstream signaling to cAMP are proposed for the suppression of inflammation, although the precise mechanism is unclear (10,12,(14)(15)(16). COX-2 is also overexpressed in various forms of cancer, and PGE2 produced by COX-2 has been implicated in the exacerbation of cancer (11,13).…”