Abstract
PGE2 is a lipid mediator of the initiation and resolution phases of inflammation, as well as a regulator of immune system responses to inflammatory events. PGE2 is produced and sensed by T cells, and autocrine or paracrine PGE2 can affect T cell phenotype and function. In this study, we use a T cell-dependent model of colitis to evaluate the role of PGE2 on pathological outcome and T-cell phenotypes. CD4+ T effector cells either deficient in mPGES-1 or the PGE2 receptor EP4 are less colitogenic. Absence of T cell autocrine mPGES1-dependent PGE2 reduces colitogenicity in association with an increase in CD4+RORγt+ cells in the lamina propria. In contrast, recipient mice deficient in mPGES-1 exhibit more severe colitis that corresponds with a reduced capacity to generate FoxP3+ T cells, especially in mesenteric lymph nodes. Thus, our research defines how mPGES-1-driven production of PGE2 by different cell types in distinct intestinal locations impacts T cell function during colitis. We conclude that PGE2 has profound effects on T cell phenotype that are dependent on the microenvironment.
Highlights
Prostaglandin E2 (PGE2) is an eicosanoid that modulates diverse physiologic and pathologic functions
To avoid undesired effects associated with dysregulated inflammation, PGE2 tissue concentrations are tightly regulated by expression of constitutive (COX1) and inducible (COX2, mPGES1) biosynthetic enzymes, as well as degradative enzymes (15-PGDH) [1, 2] and the transporters multiple drug resistance-associated protein 4 (MRP4) and prostaglandin transporter (PGT)
To address this and to evaluate how baseline production of PGE2 is influenced by both biosynthetic enzymes and by the presence of lymphocytes, we cultured colon explants of untreated Rag1−/−, mPGES-1−/−, or Rag1−/− × mPGES-1−/− double knockout mice overnight and their supernatants were assessed for PGE2 concentration
Summary
Prostaglandin E2 (PGE2) is an eicosanoid that modulates diverse physiologic and pathologic functions. To avoid undesired effects associated with dysregulated inflammation, PGE2 tissue concentrations are tightly regulated by expression of constitutive (COX1) and inducible (COX2, mPGES1) biosynthetic enzymes, as well as degradative enzymes (15-PGDH) [1, 2] and the transporters multiple drug resistance-associated protein 4 (MRP4) and prostaglandin transporter (PGT). MPGES1, an inducible enzyme often co-regulated with COX-2, acts downstream of COX enzymes to generate PGE2, and does not directly generate other prostaglandins that are derived from the shared PGH2 intermediate metabolite. Part of the variety of effects that can be triggered by PGE2 are due to its 4 known receptors (EP1-4), which display different PGE2 binding affinities and a range of tissue and cell-specific expression. PGE2 signaling in T cells is almost exclusively transduced through the EP2 and EP4 receptors [5, 6]
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