Prostaglandin E2-EP4 signaling promotes immune inflammation through Th1 cell differentiation and Th17 cell expansion.
Two distinct helper T (TH) subsets, TH1 and TH17, mediate tissue damage and inflammation in animal models of various immune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases and allergic skin disorders. These experimental findings, and the implication of these TH subsets in human diseases, suggest the need for pharmacological measures to manipulate these TH subsets. Here we show that prostaglandin E2 (PGE2) acting on its receptor EP4 on T cells and dendritic cells not only facilitates TH1 cell differentiation but also amplifies interleukin-23-mediated TH17 cell expansion in vitro. Administration of an EP4-selective antagonist in vivo decreases accumulation of both TH1 and TH17 cells in regional lymph nodes and suppresses the disease progression in mice subjected to experimental autoimmune encephalomyelitis or contact hypersensitivity. Thus, PGE2-EP4 signaling promotes immune inflammation through TH1 differentiation and TH17 expansion, and EP4 antagonism may be therapeutically useful for various immune diseases.
Yao
Chengcan
C
Department of Pharmacology, Faculty of Medicine, Kyoto University, Kyoto, Japan.
Sakata
Daiji
D
Esaki
Yoshiyasu
Y
Li
Youxian
Y
Matsuoka
Toshiyuki
T
Kuroiwa
Kenji
K
Sugimoto
Yukihiko
Y
Narumiya
Shuh
S
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D003877:Dermatitis, Contact / Q000276:immunology; D015232:Dinoprostone / Q000276:immunology* / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology*; D053759:Interleukin-23 / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D018078:Receptors, Prostaglandin E / Q000276:immunology* / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism
D020381:Interleukin-17; D053759:Interleukin-23; C545650:PTGER4 protein, human; C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone