Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling

Prostaglandins, particularly prostaglandin E2 (PGE2), play an important role during inflammation. This is exemplified by the clinical use of cyclooxygenase 2 inhibitors, which interfere with PGE2 synthesis, as effective antiinflammatory drugs. Here, we show that PGE2 directly promotes differentiation and proinflammatory functions of human and murine IL-17–producing T helper (Th17) cells. In human purified naive T cells, PGE2 acts via prostaglandin receptor EP2- and EP4-mediated signaling and cyclic AMP pathways to up-regulate IL-23 and IL-1 receptor expression. Furthermore, PGE2 synergizes with IL-1β and IL-23 to drive retinoic acid receptor–related orphan receptor (ROR)-γt, IL-17, IL-17F, CCL20, and CCR6 expression, which is consistent with the reported Th17 phenotype. While enhancing Th17 cytokine expression mainly through EP2, PGE2 differentially regulates interferon (IFN)-γ production and inhibits production of the antiinflammatory cytokine IL-10 in Th17 cells predominantly through EP4. Furthermore, PGE2 is required for IL-17 production in the presence of antigen-presenting cells. Hence, the combination of inflammatory cytokines and noncytokine immunomodulators, such as PGE2, during differentiation and activation determines the ultimate phenotype of Th17 cells. These findings, together with the altered IL-12/IL-23 balance induced by PGE2 in dendritic cells, further highlight the crucial role of the inflammatory microenvironment in Th17 cell development and regulation.Prostaglandins, prostaglandin E2 (PGE2) in particular, play an important role in the regulation of inflammatory responses. PGE2 is a key mediator of pyrexia, hyperalgesia, and arterial dilation, which increases blood flow to inflamed tissues and, in combination with enhanced microvascular permeability, results in edema. The relevance of this pathway in promoting inflammation is supported by the clinical use of cyclooxygenase inhibitors, which interfere with prostaglandin synthesis and are used as effective antiinflammatory agents (1). However, PGE2 can also exert antiinflammatory properties and is a negative regulator of neutrophil, monocyte, and lymphocyte function, particularly of Th1 cells that produce IFN-γ (2). This apparent paradox has puzzled many investigators for decades. The interplay among PGE2, IL-23, and IL-1β biology may now provide an explanation of this paradox.Th17 cells have been recognized as a unique subset of effector T cells that are distinct from the Th1 and Th2 subsets (3–6), and they have been implicated as potent effectors of autoimmune disorders, such as multiple sclerosis, psoriasis, arthritis, and inflammatory bowel disease (IBD) (7–10). We and others have previously reported that IL-23 and IL-1β are crucial factors during development of human Th17 cells (9, 11, 12). In addition, IL-23 and the IL-23–dependent Th17 cell population play essential roles in chronic inflammation and autoimmunity (13).PGE2 has been shown to exacerbate inflammation and disease severity in murine models of IBD and collagen-induced arthritis through the IL-23–IL-17 pathway (14, 15). These effects have been attributed to actions of PGE2 on innate cells, as PGE2 enhances the production of IL-23 and IL-1β in macrophages and DCs, while down-regulating IL-12 production (16). A recent report has shown that PGE2, together with IL-23, favors the expansion of human Th17 cells from PBMCs, and that PGE2 enhances IL-17 production induced by IL-23 from memory CD4⁺ cells (17). However, the molecular mechanism of PGE2-mediated signaling during human Th17 cell development has not yet been examined.In this study, we show that PGE2 acts directly on both human and murine T cells to enhance Th17 development and effector cytokine production. In human T cells, PGE2 acts via the prostaglandin receptor EP2- and EP4-mediated signaling and cAMP pathways to up-regulate IL-23 and IL-1 receptor expression. Furthermore, PGE2 synergizes with IL-1β and IL-23 to drive retinoic acid receptor–related orphan receptor (ROR)-γt, IL-17, IL-17F, CCL20, and CCR6 expression, which is consistent with the previously reported Th17 phenotype (8, 18). While enhancing Th17 cytokine expression mainly through EP2, PGE2 differentially regulates IFN-γ production and inhibits production of the antiinflammatory cytokine IL-10 in both naive and memory Th17 cells predominantly through EP4. Hence, the combination of inflammatory cytokines and noncytokine immunomodulators, such as PGE2, during differentiation and activation determines the ultimate phenotype of Th17 cells. These findings, together with the altered IL-12/IL-23 balance induced by PGE2 in dendritic cells, further highlight the crucial role of the inflammatory microenvironment in Th17 cell development and regulation.