The local and systemic production of prostaglandin E2 (PGE2) and its actions in phagocytes lead to immunosuppressive conditions. PGE2 is produced at high levels during inflammation, and its suppressive effects are caused by the ligation of the E prostanoid receptors EP2 and EP4, which results in the production of cyclic AMP. However, PGE2 also exhibits immunostimulatory properties due to binding to EP3, which results in decreased cAMP levels. The various guanine nucleotide-binding proteins (G proteins) that are coupled to the different EP receptors account for the pleiotropic roles of PGE2 in different disease states. Here, we discuss the production of PGE2 and the actions of this prostanoid in phagocytes from different tissues, the relative contribution of PGE2 to the modulation of innate immune responses, and the novel therapeutic opportunities that can be used to control inflammatory responses. 1. General Considerations Prostaglandins (PGs) are lipid mediators derived from arachidonic acid (AA) metabolism via the activation of the cyclooxygenase (COX) pathway, that regulates inflammation, immune response, hematopoiesis, tissue injury and repair, and bone resorption. PGs are found in most tissues and organs, and the variety of effects that they can elicit reflects the presence of specific PG receptors in many cell types. Upon cell activation by microbial products, cytokines, and opsonins, cytosolic phospholipase A2 (PLA2) is activated and recruited to hydrolase plasma cell phospholipids. Once it is released from the membrane, AA is rapidly converted into PGs by cells expressing prostaglandin H synthase (COX). At least two COX isoforms exist, the constitutive (COX-1) and inducible (COX-2) isoforms. COX-1 is expressed in many cell types distributed throughout the body, whereas COX-2 expression is highly restricted under basal conditions and upregulated during inflammation in different cell types [1] (see Figure 1). COX proteins are the major targets of nonsteroidal anti-inflammatory drugs (NSAIDs). Figure 1: Prostanoid biosynthesis and receptors. Upon cell stimulation, PLA2 is activated, and (AA) is released from the cellular membranes. AA is then metabolized by COX-1 or COX-2 in different cellular compartments and further metabolized by different synthases, which leads to the generation of different prostanoids. Once the product is formed, different prostanoids are transported outside the cells to bind to their respective receptors. (PG prostaglandin; Tx thromboxane; P G J 2 15-deoxy-Δ 12,14-prostaglandin J 2 ; Cox-1/2 cyclooxygenase-1/2; PGDS, PGES,
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