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 E2 (PGE2) 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 PGE2 in T-cell activation, proliferation, differentiation and migration. However, the past decade has seen a revolution in this perspective, since nanomolar concentrations of PGE2 have been shown to potentiate Th1 and Th17 responses and aid in T-cell proliferation. The understanding of concentration-specific effects of PGE2 in other cell types, the development of mice deficient in each subtype of the PGE2 receptors (EP receptors) and the delineation of signalling pathways mediated by the EP receptors have enhanced our understanding of PGE2 as an immune-stimulator. PGE2 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 PGE2 and whether it is a homeostatic or inflammatory scenario. In this review, we compartmentalize the various aspects of this complex relationship of PGE2 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.

Resistance of cyclooxygenase-2 expressing pancreatic ductal adenocarcinoma cells against γδ T cell cytotoxicity

“…In light of our observations that Colo357 PDAC cells co-cultured with gd T cells displayed enhanced production of PGE2 and intracellular Cox-2 expression taken together with reports by others that Cox-2 expression can be stimulated by various antigens and cytokines, 1,6,22 we next set out to investigate the role of cytokines on the regulation of Cox-2 expression in Colo357 cells. We focused on tumor necrosis factor a .TNFa/ as well as interferon g .IFNg/ because gd T cell lines produce both cytokines after activation with PAg, such as BrHPP.…”

“…9 Activation of EP2 as well as the EP4 receptor induces adenylate cyclase and thereby the concomitant increase in the secondary messenger cAMP. 6,30,31 Subsequently, cAMP mediates the dissociation of the regulatory and catalytic subunits of protein kinase A, which subsequently initiates the corresponding transactivation of the transcription factor cAMP responsive element binding (CREB). 32 CREB proteins are essential regulators for T-cell function and cytokine production (e.g., of IFNg).…”

“…[3][4][5] Cox-2 overexpression leads to an enhanced production of prostaglandin E2 (PGE2), which is involved in tumor progression as well as in tumor evasion of immunosurveillance. 6 The release of PGE2 by cancer cells induces and recruits regulatory T cells to the tumor site and suppresses immune responses of CD8 C ab T cells and natural killer (NK) cells as well as maturation of dendritic cells. 2,7,8 Similar to ab T cells, the function of the numerically small population of gd T lymphocytes is also inhibited by PGE2 secreting and Cox-2 expressing mesenchymal stem cells involved in the development of tumor-promoting cancer stroma.…”

Synovial Fibroblasts Directly Induce Th17 Pathogenicity via the Cyclooxygenase/Prostaglandin E2 Pathway, Independent of IL-23

“…Upregulation of COX-2 induction and PGE 2 production occurs in response to proinflammatory stimuli, including IL-1b, IL-17A, and/or TNF-a (31-37). PGE 2 , via receptor binding (EP1, EP2, EP3, and EP4), induces production of proinflammatory cytokines (28,29). PGE 2 has a pathogenic role in murine inflammatory disease models, possibly via the IL-23/IL-17 axis (38)(39)(40).…”

“…PGE 2 is produced when arachidonic acid is converted by cyclooxygenase (COX), which has two isoforms. COX-1 is expressed constitutively; COX-2 is inducible and is upregulated at inflammation and infection sites (28)(29)(30). Upregulation of COX-2 induction and PGE 2 production occurs in response to proinflammatory stimuli, including IL-1b, IL-17A, and/or TNF-a (31-37).…”