Prostaglandin E2 and T cells: friends or foes?

Abstract

Our understanding of the key players involved in the differential regulation of T-cell responses during inflammation, infection and auto-immunity is fundamental for designing efficient therapeutic strategies against immune diseases. With respect to this, the inhibitory role of the lipid mediator prostaglandin E(2) (PGE(2)) in T-cell immunity has been documented since the 1970s. Studies that ensued investigating the underlying mechanisms substantiated the suppressive function of micromolar concentrations of PGE(2) in T-cell activation, proliferation, differentiation and migration. However, the past decade has seen a revolution in this perspective, since nanomolar concentrations of PGE(2) have been shown to potentiate Th1 and Th17 responses and aid in T-cell proliferation. The understanding of concentration-specific effects of PGE(2) in other cell types, the development of mice deficient in each subtype of the PGE(2) receptors (EP receptors) and the delineation of signalling pathways mediated by the EP receptors have enhanced our understanding of PGE(2) as an immune-stimulator. PGE(2) regulates a multitude of functions in T-cell activation and differentiation and these effects vary depending on the micro-environment of the cell, maturation and activation state of the cell, type of EP receptor involved, local concentration of PGE(2) and whether it is a homeostatic or inflammatory scenario. In this review, we compartmentalize the various aspects of this complex relationship of PGE(2) with T lymphocytes. Given the importance of this molecule in T-cell activation, we also address the possibility of using EP receptor antagonism as a potential therapeutic approach for some immune disorders.

Figure 1

EP receptors: types and signalling. The four different EP receptors are high-affinity G-protein coupled receptors characterized by the activation of different signalling pathways. EP2 and EP4 are linked to Gαs proteins and function by inducing the adenylate cyclase (AC) system and concomitant increases in the secondary messenger cAMP. cAMP acts by activating PKA, resulting in the dissociation of the regulatory and catalytic subunits of the kinase. The catalytic subunits initiate the corresponding transactivation of the transcription factor CREB. EP4 is also capable of activating the phosphatidylinositol 3 kinase (PI3K) signalling pathway by phosphorylation induced by G-protein-coupled receptor kinases. This ultimately results in the triggering of NF-κB-mediated transcription programs. EP3 isoforms differ in their ability to modulate signal transduction. EP3α and EP3β are capable of blocking induction of AC while EP3γ potentiates AC and cAMP production. EP1, on the other hand, couples to Gαq protein and signals through the phospholipase C (PLC)/inositol-1,4,5-trisphosphate (IP3) pathway resulting in the formation of the second messengers diacylglycerol (DAG) and IP3, with the latter rapidly liberating Ca²⁺ ions from intracellular stores.

Figure 2

Negative regulation of T-cell responses by PGE₂. PGE₂ mediates its anti-inflammatory effects on T cells through different mechanisms: (i) PGE₂ has been shown to induce differentiation of FOXP3⁺CD4⁺CD25⁺ adaptive regulatory T cells that were found to inhibit effector T-cell responses, (ii) PGE₂ has also been demonstrated to suppress T-cell proliferation through different mechanisms, (iii) PGE₂ is involved in the inhibition of secondary messenger generation including the abrogation of Ca²⁺, K⁺, diacylglycerol (DAG) and IP production, (iv) T-cell anergy has been known to be promoted by high concentrations of PGE₂, (v) PGE₂ favors cell survival by blocking activation-induced apoptosis, cellular cytotoxicity and caspase activation, (vi) PGE₂ at micromolar concentrations was found to be inhibitory for Th1 differentiation and beneficial for Th2 differentiation, (vii) modulation of TCR-mediated signal transduction pathways by PGE₂. (a) regulation of Csk, (b) hematopoietic protein tyrosine phosphatase (HePTP) phosphorylation by cAMP-dependent protein kinase and promotion of prolactin expression, (c) interference of PKC signalling, (d) attenuation of p59(fyn) protein tyrosine kinase activity, (e, f) negative regulation of extracellular signal-regulated protein kinase (ERK) and mitogen-activated protein kinase (MAPK) pathways (g) PKA-mediated signalling potentiates T-cell factor (Tcf)/lymphoid enhancer factor (Lef) signalling pathways, (h) while PI3K inhibits glycogen synthase kinase-3 (GSK3) signal-mediation.

Figure 3

Positive regulation of T-cell responses by PGE₂. PGE₂ has diverse pro-inflammatory effects on T cells. (a) Nanomolar physiological concentrations of PGE₂ induce phosphatidylinositol 3 kinase (PI3K)/Akt signalling pathways through the EP4 receptor that serve to promote Th1 differentiation patterns. (b) PGE₂ has also been shown to potentiate Th17 differentiation through EP2-cAMP-PKA signalling pathways, primarily through (c) induction of IL-1β and IL-23 receptor (d) PGE₂ has been demonstrated to induce co-stimulatory molecules on the surface of DCs, thereby promoting T-cell proliferation. It has also been shown to promote secretion of specific cytokines by DCs, for example, IL-12, which further directs Th1 differentiation and IL-23, which enhances Th17 polarization.