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Review
, 188 (1), 21-8

Regulation of Immune Responses by Prostaglandin E2

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Review

Regulation of Immune Responses by Prostaglandin E2

Pawel Kalinski. J Immunol.

Abstract

PGE(2), an essential homeostatic factor, is also a key mediator of immunopathology in chronic infections and cancer. The impact of PGE(2) reflects the balance between its cyclooxygenase 2-regulated synthesis and 15-hydroxyprostaglandin dehydrogenase-driven degradation and the pattern of expression of PGE(2) receptors. PGE(2) enhances its own production but suppresses acute inflammatory mediators, resulting in its predominance at late/chronic stages of immunity. PGE(2) supports activation of dendritic cells but suppresses their ability to attract naive, memory, and effector T cells. PGE(2) selectively suppresses effector functions of macrophages and neutrophils and the Th1-, CTL-, and NK cell-mediated type 1 immunity, but it promotes Th2, Th17, and regulatory T cell responses. PGE(2) modulates chemokine production, inhibiting the attraction of proinflammatory cells while enhancing local accumulation of regulatory T cells cells and myeloid-derived suppressor cells. Targeting the production, degradation, and responsiveness to PGE(2) provides tools to modulate the patterns of immunity in a wide range of diseases, from autoimmunity to cancer.

Figures

Figure 1
Figure 1. Regulation of PGE2 synthesis, degradation, and responsiveness to PGE2
PGE2 synthesis is initiated by the (glucocorticosteroids sensitive) phospholipase A2-driven release of arachidonic acid (AA) from cell membranes. AA becomes the substrate for COX1 (constitutive activity) and COX2 (inducible) that convert AA to prostaglandin H2 (process that can be suppressed by NSAIDs), which is then converted to biologically-active PGE2 by PGE synthases. PGE2 signals via four known receptors (EP1-EP4), with the cAMP/PKA/CREB signaling pathway responsible for major suppressive and regulatory functions of PGE2. Local PGE2 degradation is regulated by 15-PGDH. Dark-green arrows: Currently-applied inhibitory drugs; Light green arrows: Potential targets for prospective drugs; (+) activating (−) inhibitory.
Figure 2
Figure 2. Regulation of the immune response by PGE2
PGE2 supports local acute inflammation and phagocyte-mediated immunity at the site of pathogen’s entry, while selectively suppressing the CTL-, Th1- and NK cell-mediated type-1 (cytotoxic) forms of immunity, at the stage of their induction in lymphoid tissues and by differentially regulating the influx and activity of the effector- versus regulatory cells into affected tissues. ↑ Enhancement; ↓Suppression; Blue: Relevant to immunity against intracellular pathogens and cancer; Green: Relevant to immunity against extracellular pathogens; Purple: Relevant to immune suppression. MC: mast cells; Mf: macrophages; N: neutrophils.

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