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-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.
Boniface
Katia
K
Department of Immunology, Schering-Plough Biopharma, Palo Alto, CA 94304, USA.
Bak-Jensen
Kristian S
KS
Li
Ying
Y
Blumenschein
Wendy M
WM
McGeachy
Mandy J
MJ
McClanahan
Terrill K
TK
McKenzie
Brent S
BS
Kastelein
Robert A
RA
Cua
Daniel J
DJ
de Waal Malefyt
René
R
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D018920:Coculture Techniques; D000242:Cyclic AMP / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000494:pharmacology; D053759:Interleukin-23 / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D018448:Models, Immunological; D054399:Receptors, CCR6 / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000187:drug effects*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D020381:Interleukin-17; D053583:Interleukin-1beta; D053759:Interleukin-23; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; C545645:Ptger2 protein, mouse; C545651:Ptger4 protein, mouse; D054399:Receptors, CCR6; D017472:Receptors, Interleukin-1; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D016753:Interleukin-10; D007371:Interferon-gamma; D000242:Cyclic AMP; D015232:Dinoprostone