Prostaglandin E2 as a Regulator of Immunity to Pathogens

Abstract

The body is exposed to foreign pathogens every day, but remarkably, most pathogens are effectively cleared by the innate immune system without the need to invoke the adaptive immune response. Key cellular components of the innate immune system include macrophages and neutrophils and the recruitment and function of these cells are tightly regulated by chemokines and cytokines in the tissue space. Innate immune responses are also known to regulate development of adaptive immune responses often via the secretion of various cytokines. In addition to these protein regulators, numerous lipid mediators can also influence innate and adaptive immune functions. In this review, we cover one particular lipid regulator, prostaglandin E₂ (PGE₂) and describe its synthesis and signaling and what is known about the ability of this lipid to regulate immunity and host defense against viral, fungal and bacterial pathogens.

Keywords: adaptive immunity; eicosanoids; host defense; inflammation; innate immunity; pathogen.

Figure 1. Prostaglandins and leukotrienes synthesis

Phospholipases release arachidonic acid (AA) from the phospholipid membrane. Free AA can then be modified by the cyclooxygenase or the lipoxygenase pathway to produce prostaglandins and leukotrienes, respectively. During the cyclooxygenase pathway, to the left, COX enzymes modify AA to produce PGH₂, which can then be modified by specific enzymes to produce PGI₂, TXA₂, PGD₂, PGE₂, and PGF_2α. COX enzymes can be blocked by the nonsteroidal anti-inflammatory drugs, indomethacin and aspirin. Prostaglandins are known inhibitors of the antimicrobial function of both macrophages (Mϕ) and polymorphonuclear leukocytes (PMN). The lipoxygenase pathway, to the right, leads to the production of LTA₄ which can then be modified by specific enzymes to produce LTB₄ or LTE₄. Leukotrienes are known to promote Mϕ and PMN antimicrobial functions.

Figure 2. Prostaglandin E₂ signaling

Upon secretion, PGE₂ can signal trough 4 different GPCRs subtypes termed EP1-4 or get degraded to its inactive metabolite, 14-Keto-PGE₂. The EP1 receptor is coupled to the Gaq subunit which leads to the increase of intracellular Ca²⁺ levels. EP2 and EP4 are coupled to Gas while EP3 can couple to Gi, Gas or G12/13. EP1 is known to induce NFkB and NFAT transcription factors, while EP2 and EP4 can induce NFkB and CREB. When EP3 is coupled to Gas, it can induce NFkB/CREB, but when coupled to Gi, it can inhibit these factors. Figure created using ScienceSlides.

Figure 3. PGE₂ effects on immune cells

(From left to right) Macrophages, dendritic cells, neutrophils and T cells. The known effects of PGE₂ on these cells are summarized below each cell. Symbol meaning: ↑ increase/activation; ↓ decrease; ˧ inhibits. Figure created using ScienceSlides.