The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20082293
The Journal of Experimental Medicine, Vol. 206, No. 3, 535-548
The Rockefeller University Press, 0022-1007 $30.00
© Boniface et al.
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ARTICLE

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

Katia Boniface1, Kristian S. Bak-Jensen1, Ying Li1, Wendy M. Blumenschein2, Mandy J. McGeachy1, Terrill K. McClanahan2, Brent S. McKenzie1, Robert A. Kastelein1, Daniel J. Cua1, and René de Waal Malefyt1

Departments of 1 Immunology and 2 Experimental Pathology and Pharmacology, Schering-Plough Biopharma, Palo Alto, CA 94304

CORRESPONDENCE René de Waal Malefyt: rene.de.waal.malefyt{at}spcorp.com OR Daniel J. Cua: daniel.cua{at}spcorp.com

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)-{gamma}t, 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.

K.S. Bak-Jensen's present address is Dept. of Diabetes Protein Engineering, Novo Nordisk A/S, DK-2760 Måløv, Denmark.

B.S. McKenzie's present address is CSL Ltd. Bio21 Institute, Parkville, Victoria, Australia 3020.

Daniel J. Cua and René de Waal Malefyt contributed equally to this paper.

Abbreviations used: COX2, cyclooxygenase 2; CRE, cAMP-responsive element; IBD, inflammatory bowel disease; PGE2, prostaglandin E2; ROR, retinoic acid receptor–related orphan receptor.

© 2009 Boniface et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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