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 differentiatio...

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Bibliographic Details
Published in:	The Journal of experimental medicine 2009-03, Vol.206 (3), p.535-548
Main Authors:	Boniface, Katia, Bak-Jensen, Kristian S, Li, Ying, Blumenschein, Wendy M, McGeachy, Mandy J, McClanahan, Terrill K, McKenzie, Brent S, Kastelein, Robert A, Cua, Daniel J, de Waal Malefyt, René
Format:	Article
Language:	eng
Subjects:	Animals Cell Differentiation - drug effects Coculture Techniques Cyclic AMP - metabolism Dinoprostone - pharmacology Gene Expression Regulation - drug effects Humans Immunologic Memory - drug effects Interferon-gamma - biosynthesis Interleukin-10 - biosynthesis Interleukin-17 - biosynthesis Interleukin-1beta - pharmacology Interleukin-23 - genetics Interleukin-23 - pharmacology Mice Models, Immunological Receptors, CCR6 - metabolism Receptors, Interleukin-1 - genetics Receptors, Prostaglandin E - genetics Receptors, Prostaglandin E - metabolism Receptors, Prostaglandin E, EP2 Subtype Receptors, Prostaglandin E, EP4 Subtype Signal Transduction - drug effects T-Lymphocytes, Helper-Inducer - cytology T-Lymphocytes, Helper-Inducer - drug effects Up-Regulation - drug effects
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Summary:	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-1beta and IL-23 to drive retinoic acid receptor-related orphan receptor (ROR)-gammat, 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)-gamma 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.
ISSN:	0022-1007 1540-9538