Prostaglandin E2 As a Modulator of Viral Infections

Abstract

Viral infections are a major cause of infectious diseases worldwide. Inflammation and the immune system are the major host defenses against these viral infection. Prostaglandin E₂ (PGE₂), an eicosanoid generated by cyclooxygenases, has been shown to modulate inflammation and the immune system by regulating the expression/concentration of cytokines. The effect of PGE₂ on viral infection and replication is cell type- and virus-family-dependent. The host immune system can be modulated by PGE₂, with regards to immunosuppression, inhibition of nitrogen oxide (NO) production, inhibition of interferon (IFN) and apoptotic pathways, and inhibition of viral receptor expression. Furthermore, PGE₂ can play a role in viral infection directly by increasing the production and release of virions, inhibiting viral binding and replication, and/or stimulating viral gene expression. PGE₂ may also have a regulatory role in the induction of autoimmunity and in signaling via Toll-like receptors. In this review the known effects of PGE₂ on the pathogenesis of various infections caused by herpes simplex virus, rotavirus, influenza A virus and human immunodeficiency virus as well the therapeutic potential of PGE₂ are discussed.

Keywords: immunity; inflammation; prostaglandin E2; therapeutic agents; viral infection.

Figure 1

The biosynthesis pathway of PGE₂. (A) Production of PGE2 is initiated with the liberation of AA by cPLA₂. Arachidonic acid can then enter one of three pathways. (B) Lipoxygenase (LOX) converts AA to hydroperoxyeicosatetraenoic acid (HPETE) which is converted to leukotriene A₂ (LTA₂) and is further converted in the remainder of the leukotriene family (B₄–E₄) which are mainly responsible for lipid signaling. (C) Cytochrome P450 can also use AA as substrate which subsequently produces 16, 20- hydroxyicosatetraenoic acid (HETE) and 14, 15-epoxyeicosatrienoic acid (EET) which function in autocrine and paracrine signaling. (D) Arachidonic acid is converted to PGH₂ by die COX isoenzymes. (E) Prostaglandin H₂ is the precursor for all the other prostaglandins and can be converted into PGE₂ (via PGE2 synthase [cPGES, mPGES-1 and mPGES-2)], PGD₂ (PGD₂ synthase), PGI₂ (Prostacyclin synthase), TXA₂ (TX synthase) which functions as a vasoconstrictor. (F) PGF_2α can be produced from PGH₂ directly by endoproxide reductase or form PGE₂ via 9-ketoreductase. Adapted from Jenkins et al. (2009).

Figure 2

PGE₂-EP receptor signaling pathways. Following the synthesis of PGE₂, the prostanoid is exported and signals via four known receptors (EP1–EP4). The receptors then active cAMP/PKA/CREB signaling pathways which are responsible for the major suppressive and regulatory functions of PGE₂. Adapted from Nasrallah et al. (2014) and Sugimoto and Narumiya (2007).

Figure 3

The interaction between the innate and adaptive immunity in the presence of pathogens. (A) Upon viral infection the infected cell presents the viral antigen on the major histocompatibility complex (MHC)-I. (B) Cytotoxic T cells (Tc) and natural killer cells (NK) can then bind to these viral antigens and (C) lead to the destruction of the cell. (D) Viral particles neutralized by pre-existing antibodies can be engulfed by macrophages via antibody neutralization. (E) This leads to viral antigens being presented by dendritic cells (DC), shown in blue on MHC-ll and the resulting antigen presenting cells (APC) activating Tc and NK and releasing cytokines. (F) T helper cells bind to these viral antigens and differentiate into Th1 or Th2 responses. T helper cells are also responsible for the activation of B cells. (G) The B cells transform into plasma cells which start producing antibodies specific toward the antigen and differentiate into B memory cells. (H) Toll-like receptors are an integral part of the innate immunity and function via two pathways activating NFκB, mitogen-activated kinases and type I IFN. (I). The complement system composes of different pathways that lead to the destruction of infected cells. Adapted from Rouse and Sehrawat (2010).

Figure 4

Effect of PGE₂ on immune responses. Prostaglandin E₂ suppresses the Th1- and natural killer (NK) cell-mediated type I form of immunity at their sites of induction, while supporting local acute inflammation and phagocyte mediated immunity. Prostaglandin E₂ regulates the influx and activity of the effector vs. the regulatory cells into affected tissues. Purple indicates effects on immune suppression; blue indicates effects on immunity against intracellular pathogens, while green indicates effects on extracellular pathogens; ↑ increase; ↓ decrease. Interleukin (IL), interferon (IFN), tumor necrosis factor (TNF), Immunoglobulin (Ig). Toll-like receptors (TLRs) Adapted from Kalinski (2012).